METHODS OF IDENTIFYING GABAB RECEPTOR SUBTYPE-SPECIFIC AGONISTS

Abstract: Methods for identifying substances that are agonists of GABAB receptors that are heteromers of gb1a and gb2 subunits where the substances are not agonists of GABAB receptors that are heteromers of gb1b and gb2 subunits or gb1c and gb2 subunits are provided. The substances are useful for the treatment of a variety of conditions, <i>e.g.</i>, epilepsy and certain pain syndromes.

Description: TITLE OF THE INVENTION METHODS OF IDENTIFYING GABAB RECEPTOR SUBTYPE-SPECIFIC AGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 60/ 285,969, filed April 24, 2001, which is a Continuation-In-Part of U.S. Provisional Application No. 60/212,426, filed June 19, 2000, which is a Continuation-In-Part of U.S. Provisional Application No. 60/212,152, filed June 16, 2000, the contents of which are incorporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY-SPONSORED R&D Not applicable. REFERENCE TO MICROFICHE APPENDIX Not applicable. FIELD OF THE INVENTION The present invention provides methods for identifying substances that are agonists of GABAB receptors that are heteromers of gbla and gb2 subunits where the substances are not agonists of GABAB receptors that are heteromers of gblb and gb2 subunits or gblc and gb2 subunits. Nor are the substances agonists or GABAB receptors comprising other alternative gbl isoforms with gb2 subunits. BACKGROUND OF THE INVENTION GABA (γ-amino-butyric acid) is the most widely distributed amino acid inhibitory neurotransmitter in the vertebrate central nervous system. The principal physiological role of GABA in the neural axis is synaptic inhibition. The biological activities of GABA are mediated by three types of GABA receptors: ionotropic GABAA receptors, metabotropic GABAB receptors, and ionotropic GABAc receptors. GABAA receptors convey fast synaptic inhibition by activating a postsynaptic chloride conductance that is allosterically modulated by benzodiazepines, barbituates, and neurosteroids (Mody et al., 1994, Trends Neurosci. 17:517-525). GABAB receptors mediate the slower, longer lasting synaptic inhibitory actions implicated in hippocampal long term potentiation, slow-wave sleep, J. Pharmacol. Exp. Ther. 292:2-7 and references therein). GABAB receptors play a role in the mediation of late inhibitory postsynaptic potentials (IPSPs) by mediating slow synaptic inhibition by GABA via G-proteins. This is thought to result from the activation of K+ channels (Mody et al., 1994, Trends Neurosci. 17:517-525). Presynaptic GABAB receptor activation has generally been reported to result in the inhibition of Ca2+ conductance, leading to a decrease in the evoked release of neurotransmitters (Andrade et al., 1986, Science 234:1261-1265; Takahashi et al., 1998, J. Neurosci. 18:3138-3146). Many of the physiological roles of GABAB receptors can be attributed to the modulation of P/Q (o A, o^δ, βi subunits), and N- type (αiB. ^2 , βl subunits) voltage-dependent calcium channels (VD-CCs) by presynaptic receptors and modulation of inwardly rectifying K+ channels (GIRKs) by postsynaptic GABAB receptors (Bowery & Enna, 2000, J. Pharmacol. Exp. Ther. 292:2-7 and references therein). It has been suggested that pharmacologically distinct receptor subtypes mediate pre- and postsynaptic actions (Wojcik & Neff, 1984, Mol. Pharmacol. 25:24-28; Bonanno et al., 1997, Br. J. Pharmacol. 120:60-64: Bonanno & Raiteri, 1993, J. Pharmacol. Exp. Ther. 265:765-768; for a review see Kerr & Ong, 1995), but this has not been revealed by molecular studies to date. GABAB receptor regulation of VD-CC function is thought to be mediated by G-protein βγ subunits via a membrane delimited mechanism (Herlitze et al., 1996, Nature 380:258-262; Ikeda et al., 1996, Nature 380:255-258) resulting in the inhibition of membrane Ca2+ conductance and a decrease in neurotransmitter release (Doze et al., 1995, J. Neurophysiol. 74:43-53; Wu & Saggau, 1997, Trends Neurosci. 20:204-212). Activation of presynaptic GABAB receptors negatively coupled to VD-CCs is likely the mechanism underlying the anti-nociceptive effects of GABA and the prototypic nonselective GAB Aβ receptor agonist baclofen which have been reported to inhibit the release of pain transmitters such as calcitonin gene-related peptide and substance P in spinal cord slices (Malcangio & Bowery, 1993, J. Pharmacol. Exp. Ther. 266:1490-1496). Baclofen has also been reported to be efficacious when given intrathecally for the treatment of central pain following stroke or spinal cord injury (Loubser & Akman, 1996, Pain Sympt. Mgmt. 12:241-247). However, its wider clinical use has been limited because doses (p.o.) needed for efficacy are associated with flaccidity and hypotonia. GABAβ receptors belong to the superfamily of seven transmembrane- spanning G-protein coupled receptors that are coupled to neuronal K+ or Ca2+ channels. GABAB receptor activation increases K+ or decreases Ca2+ conductance and also inhibits or potentiates stimulated adenylyl cyclase activity. The expression of GABAβ receptors is widely distributed in the mammalian neural axis (e.g., frontal cortex, hippocampus, cerebellum, thalamus, spinal cord, dorsal root ganglia and has been observed in many peripheral organs as well (Belley et al., 1999, Biorg. Med. Chem. 7:2697-2704). A large number of pharmacological activities have been attributed to GABAβ receptor activation, e.g., analgesia; hypothermia; catatonia; hypotension; reduction of memory consolidation and retention; and stimulation of insulin, growth hormone, and glucagon release (see Bowery, 1989, Trends Pharmacol. Sci. 10:401- 407 for a review). It is well accepted that GABAB receptor agonists and antagonists are pharmacologically useful in indications such as stiff man syndrome, gastroesophogeal reflux, neuropathic pain, incontinence and treatment of cough and cocaine addiction. For example, the GABAB receptor agonist (-)baclofen, as part of a racemic mixture with (+)baclofen, a structural analog of GABA, is a clinically effective muscle relaxant (Bowery & Pratt, 1992, Arzneim.-Forsch./Drug Res. 42:215-223). -(±)baclofen, has been sold in the United States as a muscle relaxant under the name LIORESAL® since 1972. Functional GABAB receptors are formed following the co-expression of two protein subunits having characteristics similar to those of the metabotropic glutamate receptors, viz., a signal peptide sequence followed by a large N-terminal domain believed to represent a ligand binding pocket that shares structural similarity to bacterial perisplasmic leucine, isoleucine, valine binding LIV-BP proteins. This putative extracellular ligand binding domain precedes seven transmembrane spanning domains. The hallmark seven transmembrane spanning domains are typical of G- protein coupled receptors (GPCRs), although metabotropic glutamate receptors and GABAβ receptor proteins are considerably larger than most GPCRs. Recombinant expression of the two GABAB receptor gbl and gb2 subunit proteins, either together or separately, demonstrated that functional GABAB receptors were formed only when both proteins were expressed in the same cell, most likely as heterodimers (Jones et al., 1998, Nature 396:674-679; White et al., 1998, Nature 396:679-682; Kaupmann et al, 1998, Nature 396:683-687; Kuner et al., 1999, Science 283:74-77; Ng et al., 1999, J. Biol. Chem. 274:7607-7610; and International Patent Publication WO 99/40114). The GABAβ receptor heterodimer is composed of a subunit known as GABAβRla (or a splice variant known as GABAβRlb) (Kaupmann et al., 1997, Nature 386:239-246) together with a subunit known variously as GABAβR2 (White et al., 1998, Nature 396:679-682; Jones et al., 1998, Nature 396:674-679), GBR2 (Kuner et al., 1999, Science 283:74-77), gb2 (Ng et al., 1999, J. Biol. Chem. 274;7607-7610; or HG20 (International Patent Publication WO 99/40114). A third splice variant of GABAβRla has been reported by Ng et al., 2001, Mol Pharm. 59:144-152. This third variant is known as gblc, in keeping with the terminology used by Ng et al. in which GABAβRla is referred to as gbla and GABAβRlb is referred to as gblb. The GABAB receptor heterodimer is generally accepted to be the functional GAB Aβ receptor. However, it remains possible that GABAB receptor monomers or homodimers are functional when in certain cellular environments (Kuner et al, 1999, Science 283:74-77; Kaupmann et al., 1997, Nature 386:239-246; Kaupmann et al., 1998, Nature 396:683-687). Gabapentin (NEURONTIN®, l-(aminomethyl)cyclohexaneacetic acid) was developed as a brain penetrant structural analog of GABA to treat spasticity and to reduce polysynaptic spinal reflexes (reviewed by Bryans & Wustrow, 1999, Med. Res. Rev. 19:149-177 and references therein). Gabapentin is an anticonvulsant used for the treatment of refractory partial seizures and secondary generalized tonic- clonic seizures. It has been proposed to have mood-stabilizing properties and may be useful in certain neuropathies such as diabetic neuropathy or post-herpetic neuralgia. Gabapentin monotherapy appears to be efficacious for the treatment of pain and sleep interference associated with diabetic peripheral neuropathy and exhibits positive effects on mood and quality of life (Rowbotham et al., 1998, J. Am. Med. Assn. 280: 1837-1842). Gabapentin is also effective in the treatment of post-herpetic neuralgia (PHN), a syndrome of often intractable neuropathic pain following herpes zoster (shingles) that eludes effective treatment in many patients. Mood and quality of life of PHN patients also improve with gabapentin therapy (Rowbotham et al., 1998, J. Am. Med. Assn. 280:1831 : 1836). Gabapentin has been shown to be effective in reducing the number of partial seizures in patients with drug-resistant partial epilepsy (U.K. Gabapentin Study Group, 1990, Lancet, 335:1114-1117). Gabapentin has been studied for use in neurodegenerative disorders such amyotrophic lateral sclerosis, cocaine addiction and in various psychiatric disorders such as bipolar disorder and may be of use as an anxiolytic (reviewed by Bryans & Wustrow, 1999, Med. Res. Rev. 19:149-177 and references therein). It has been shown to have antihyperalgesic action in an inflammatory pain model (Field et al., 1997, Br. J. Pharmacol. 121:1519-1522). Gabapentin has been reported to inhibit K+-evoked Ca2+ rises in neocortical synaptosomes via inhibition of VD-CCs (Fink et al., 2000, Br. J. Pharmacol. 130:900-906; Stefani et al., 1998, Neuropharmacology 37:83-91) and reduce K+-evoked glutamate release from neocortical and hippoccampal slices (Dooley et al., 2000, Neurosci. Letts. 280: 107-110). Gabapentin has also been reported to inhibit excitatory neurotransmitter release in the spinal cord dorsal horn (Shimoyama et al., 2000, Pain 85:405-414; Patel et al., 2000, Br. J. Pharmacol. 130:1731-1734). Gabapentin has recently been reported to be a selective agonist at the recombinant gbla-gb2 heterodimer and neuronal GABAB receptor coupled to GJJRKs with no partial agonist or antagonist activity at gblb-gb2 or gblc-gb2 subtypes (Ng et al., 2001, Mol Pharm. 59:144-152). Gabapentin' s mechanism of action has been the object of much study, but no consensus has arisen. Various hypotheses have been proposed. For example, Taylor et al., 1998, Epilepsy Res. 29:233-249 list the following possibilities: (1) gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine, and phenylalanine for transport; (2) gabapentin increases the concentration and probably the rate of synthesis of GABA in the brain; (3) gabapentin binds with high affinity to a binding site in brain tissues that is associated with an auxiliary subunit of voltage- sensitive calcium channels; (4) gabapentin reduces the release of several monoamine neurotransmitters; (5) gabapentin inhibits voltage-activated sodium channels; (6) gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions; and (7) gabapentin prevents neuronal death. See also Taylor, 1997, Rev. Neurol. (Paris) 153 (Suppl) S39-S45 and Brown & Gee, 1998, J. Biol. Chem. 273:25458-25465 for other references discussing possible mechanisms of action for gabapentin. Gabapentin has been reported to bind with nanomolar affinity to the auxiliary α 2 δ subunit of voltage dependent-calcium channels (VD-CCs) (Gee et al., 1996, J. Biol. Chem. 271:5768-5776). However no direct functional correlation to this binding has been reported to date, and it is unknown whether this accounts for the anti-convulsant, anti-hyperalgesic and anti-nociceptive actions of gabapentin (Taylor et al., 1998, Epilepsy Res. 29:233-249). Gabapentin has been reported to have no effect on VD-CCs in cultured rodent neurons (Rock et al., 1993, Epilepsy Res. 16:89- 98) and in acutely dissociated human dentate gyrus granule cells from patients with temporal lobe epilepsy (Schumacher et al., 1998, Epilepsia 39:355-363). Yet, gabapentin has been reported to inhibit predominantly L-type calcium currents in isolated rat neocortical, striatal, and pallidal neurons (Stefani et al., 1998, Neuropharmacology 37:83-91). More recently, gabapentin has been found to inhibit K+-evoked glutamate release from rat neocortical and hippocampal slices (Fink et al., 2000, Br. J. Pharmacol. 130:900-906; Dooley et al, 2000, Neurosci. Letts. 280: 107- 110). However, the mechanisms underlying these gabapentin actions were not elucidated. It is noteworthy that gabapentin is believed not to act through GABAβ receptors. See The Compendium of Pharmaceuticals and Specialties. Thirty-third edition, 1988, pp. 1101-1102, Canadian Pharmacists Association, Ottawa, ON, CA, where it is stated that gabapentin "does not interact with GABA receptors." See also Rowbotham. et al., 1998, J. Am. Med. Assn. 280:1837-1842, at page 1838: "Its [i.e., gabapentin' s] mechanism of action has not yet been fully elucidated, but appears not to involve binding to GABA receptors [citing Goa & Sorkin, 1993, Drugs 46:409- 427]." Field et al., 1997, Br. J. Pharmacol. 121:1513-1522 state: "Although gabapentin was originally designed as a GABA analogue which would penetrate into the CNS, it does not interact with either GABAA or GABAB receptors ..." SUMMARY OF THE INVENTION The present invention is directed to methods for identifying substances that are agonists of GABAβ receptors that are heteromers of gbla and gb2 subunits where the substances are not agonists of GAB Aβ receptors that are heteromers of gblb and gb2 subunits, gblc and gb2 subunits, or other gbl-gb2 heteromer subytpes. The substances inhibit presynaptic calcium currents, activate post-synaptic potassium currents, and inhibit somatic calcium currents. The substances are agonists of GABAβ receptors that are coupled to inwardly rectifying K+ channels in xenopus oocytes or to GABAB receptors negatively coupled to voltage dependent-calcium channels in heterologous expression systems such as HEK-293 cells and melanotroph cell lines derived from mouse intermediary lobe pituitary tumors. The substances are also agonists of G B Aβ receptors that are negatively coupled to voltage dependent- calcium channels in rat hippocampal neurons and spinal cord neurons. The substances are not agonists of GABAA receptors and exhibit more selectivity for effector pathways and a distinct mechanism of activation (e.g., rapid desensitization at the GABAβ receptor) as compared to baclofen. The combination of characteristics outlined above is possessed by gabapentin and indicates that the substances identified by the methods of the present invention represent a class of substances that, like gabapentin, are expected to be useful in the treatment of such conditions as psychiatric disorders, e.g., bipolar disorders, social phobias, and anxiety; epilepsy and other convulsant disorders; gastroesophogeal reflux; cocaine addiction; neurodegenerative disorders such as amyotrohic lateral sclerosis; and multiple chronic pain states such as diabetic neuropathy or post-herpetic neuralgia. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A shows an amino acid alignment of the extracellular N- terminal domains of the human gbla, gblb, gblc isoforms. The proposed signal peptide cleavage site of gbl is marked with scissors. Putative N-glycosylation sites (T) are indicated and arrows ( • • ) delimit the Sushi domains (SU). An arrow (-> • ) marks the start of the LIV-BP-like domain. Gaps (...) were introduced to maximize alignment. The gbla sequence shown is a portion of SEQ.ID.NO.:2. The gblc sequence shown is a portion of SEQ.ID.NO.:8. The gblb sequence shown is a portion of SEQ.ID.NO.:6. Figure IB shows the structure of the GABAB heteromer pan agonists GABA and baclofen and the gbla subtype-specific agonist gabapentin. Figure 2A-F shows modulation of Kir 3.1/3.2 in Xenopus oocytes by different gbl/gb2 heteromers. Currents were measured by holding oocytes at -80 mV. The dark bar in each trace denotes changing from perfusion of oocytes with KD-98 solutions to solution containing 100 μM GABA. The light bar denotes the beginning of perfusion with 100 μM gabapentin. Co-expression of human gb2 with mouse gbla (Figure 2A), human gbla (Figure 2B), gblb (Figure 2C) or gblc (Figure 2D). Control traces: M2 muscarinic receptor (Figure 2E) or β2AR (Figure 2F) co- expressed with Kir 3.2. In the case of the β2 adrenergic receptor it was necessary to co-express the bovine Gs subunit as well. Arrows denote different patterns of desensitization for GABA- or gabapentin-mediated receptor activation. Each trace is representative of at least four separate experiments performed on different oocytes. Figure 3A-B shows that gabapentin modulates Kir3.1/3.2 only via gbla receptor heteromers. Figure 3A shows the fold stimulation of Kir 3.1/3.2 current by gabapentin or GABA over basal current (set to 1.0). Fold stimulation was calculated by dividing maximal ligand-stimulated current by basal current measured in KD-98 solution. Note that the effects of GABA (at an identical concentration) are always significantly larger than for gabapentin. Figure 3B shows the dose-response relation for GABAg ligands at gbla/gb2. Co-expression of murine gbla and human gb2 results in the modulation of Kir 3.1/3.2 in a dose-dependent manner. Currents were measured at various doses of GABA, gabapentin or baclofen and normalized relative to the basal current. Averaged data from many experiments (minimum of n=4 for each point on the three dose-response curves) was pooled and fit to the Hill equation using GraphPad Prism v2.0. As positive controls, the response of Kir 3.2 (expressed without Kir 3.1) to M2 muscarinic receptors (1 μM carbachol, n=6) or to β2-adrenergic receptors (co-expressed with Gsα, 1 μM isoproterenol, n=17) was measured. Figure 4 shows that gabapentin activates potassium currents via GAB Aβ receptors in CA1 pyramidal cells in situ. (A) Micrograph of biocytin filled CA1 pyramidal neurons exposed to gabapentin. Calibration mark, 100 μm. (B) I-V relations were obtained during voltage ramps from -60 to -160 mV in control ACSF and in the presence of 1 mM gabapentin (Gp, Bl). Gabapentin currents (B2) were isolated by subtracting currents from I-V relations in control ACSF from those in the presence of gabapentin. The current evoked by ImM gabapentin in B2 was obtained from the traces shown in B 1. Gabapentin evoked outward currents at membrane potentials between -60 and -100 mV. In the same cell, gabapentin currents increased in magnitude with increasing doses (0.1-1 mM). (C) Bath application of 2-20 μM baclofen. elicited in CA1 pyramidal cells similar potassium currents with a comparable reversal potential. (D) The mean chord conductance (measured at -80 mV) of baclofen and gabapentin currents increased in dose-dependent fashion (the number above each bar indicates the number of cells tested). The dose-response relationship for gabapentin was shifted approximately ten-fold higher relative to that of baclofen. The mean chord conductance of gabapentin (1 mM) and baclofen (20 μM) potassium currents were blocked by the GABAβ antagonist CGP55845 (at 4 and 1 μM concentration, respectively). Figure 5 shows presynaptic GABAB inhibition of GABA synaptic transmission in hippocampus: inefficacy of gabapentin and efficacy of baclofen. (A) Experimental arrangement for evoking monosynaptic fast GABAA IPSCs by electrical stimulation of inhibitory fibers in stratum radiatum in the presence of blockers of glutamate synaptic transmission (20 μM CNQX and 50 μM AP5) during whole cell voltage clamp recording from pyramidal cells. (B) At resting membrane potential, stimulation evoked fast outward IPSCs in control ACSF (with CNQX and AP5). IPSCs were depressed during bath application of 20 μM baclofen. (C) In contrast, during bath application of 1 mM gabapentin, IPSCs were minimally affected relative to control. (D) The mean reduction of IPSCs by baclofen was dose- dependent (2-20 μM) and the presynaptic actions of 20 μM baclofen were completely antagonized by 1 μM of the GABAB antagonist CGP55845. Gabapentin, at concentrations between 0.1-1 mM, did not produce such reductions in IPSC amplitude. The numbers above the bars indicate the number of cells tested in each condition. The small mean reduction in the presence of gabapentin was not significatly different from that seen with repeated application of control ACSF (with CNQX and AP5; diagonal bars) or during application of 4 μM CGP55845. Figure 6A-B shows the cDNA sequence (SEQ.ID.NO.:l) and Figure 6C shows the amino acid sequence (SEQ.ID.NO.:2) of human gbla (GenBank accession no. AJ225028). Figure 7A-B shows the cDNA sequence (SEQ.ID.NO.:3) and Figure 7C shows the amino acid sequence (SEQ.ID.NO.:4) of murine gbla (GenBank accession no. AFl 14168). Figure 8A shows the cDNA sequence (SEQ.JD.NO.:5) and Figure 8B shows the amino acid sequence (SEQ.JJD.NO.:6) of human gblb (GenBank accession no. AJ225029). Figure 9A shows the cDNA sequence (SEQ.ID.NO.:7) and Figure 9B shows the amino acid sequence (SEQ.JJD.NO.:8) of human gblc (GenBank accession no. AJ012187). Figure 10A-B shows the cDNA sequence (SEQ.ID.NO.:9) and Figure 10C shows the amino acid sequence (SEQ.ID.NO.:10) of human gb2 (GenBank accession no. AF058795). Figure 11 shows the pharmacological actions of GABAB ligands on high K+-evoked activation of VD-CCs in mE cells endogenously expressing gbla heteromers. Panel A shows there is a sharp increase in [Ca2+] followed by a slower second peak or shoulder in responses to depolarization by high extracellular K+ concentrations. Panel B shows that baclofen (1 μM) reduces the primary response. Panel C shows that baclofen effects (1 μM) are completely reversed by addition of 3 μM CGP55845. CPG55845 (3 μM) has no significant effect on the response of mIL cells to depolarization (Panel D). Panel E shows that 1 μM gabapentin reduces the primary Ca2+ responses of cells similar to 1 μM baclofen (top middle panel) and that this reduction is also blocked by 1 μM CGP55845 (Panel F). In each panel, the individual Ca2+ responses of 6-8 cells are shown. Figure 12 shows a dose response study of the ability of gabapentin to inhibit influx of Ca2+ after high K+ depolarization. mIL cells were treated 1-5 min with the indicated doses of gabapentin, then depolarized with high K+ as described in Example 6. Bars represent the standard error for the number of cells indicated in brackets. The EC50 was calculated after fitting the data using GraphPad. Figure 13 shows that inhibition of K+-evoked calcium mobilization by 1 μM gabapentin is blocked in a dose-dependent manner with 30 nM - 3 μM CGP55845. CGP55845 and gabapentin are abbreviated CGP and GBP in the graphs respectively. Each error bar represents 1 SEM. Number of cells analyzed is noted in brackets. Figure 14 shows that antisense knockdown of the endogenous GABAβ gbla subunit in mIL cells result in the block of gabapentin-induced inhibition of the primary increase in [Ca2+]i following K+ depolarization and activation of VD-CCs. There was no significant difference among any of the control values and the values for the various ADN treatments when compared by analysis of variance; therefore the results are presented as normalized to the value for high K+ depolarization (Column A) set to 100%. Both 10 μM and 30 μM gabapentin inhibited the depolarization- induced rise in intracellular [Ca2+] (compare A to B and C). None of the deoxynucleotide treatments in themselves affected the depolarization-induced rise in intracellular [Ca2+] (compare A, D, G and J). gbla ADN treatment completely blocked the ability of gabapentin to inhibit the rise in [Ca2+]j (compare B and C to D, E and F), whereas gblb ADN at two concentrations tested had no such effect on gabapentin, being indistinguishable from control values (compare A, B and C vs. G, H and I). Treatment with the gbla mis-sense probe was also without effect when compared to control values (compare A. B and C vs J. K and D and like the ehlh sub- (C) and supra-threshold (D) evoked somatic Ca2+ responses (traces 2 vs 1), but did not prevent the generation of Ca2+ spikes when somatic current injection was increased (traces 3). Baclofen similarly reduced Ca2+ responses; subthreshold (E), suprathreshold (F). Figure 16 shows that gabapentin inhibits Ca2+ responses in a dose- dependent manner. Dose/response histograms of gabapentin (100 μM to 1 mM) actions on both membrane depolarizations (A, C) and Ca2+ responses (B, D) for sub- (A, B) and supra-threshold (C, D) current injections. In the presence of 1 mM gabapentin, cells were still able to generate Ca2+ spikes when somatic current injection was increased. In these conditions, both membrane depolarizations and Ca2+ responses were not significantly different from control. (C, D) Summary histograms of baclofen (40 μM) effects on sub- (E, G) and supra-threshold (F, H) responses. Bars on histograms represent SEM. Figure 17 shows gabapentin and baclofen inhibition of Ca2+ responses via GABAB receptor activation. In the presence of the GABAB receptor antagonist CGP55845 (4 μM), gabapentin (2 mM; A, B) and baclofen (40 μM; C, D) failed to depress responses evoked by either sub- (A, C) or supra-threshold (B, D) current injection. Summary histograms of gabapentin (2 mM) and baclofen (40 μM) effects on responses evoked by sub- (E) and supra-threshold (F) stimulation, in the absence and presence of CGP55845. DETAILED DESCRIPTION OF THE INVENTION For the purposes of describing the present invention: "gbla" refers to the human GABAB receptor subunit known as GABAβRla in Kaupmann et al., 1998, Proc. Natl. Acad. Sci. USA 95:14991-14996, the amino acid sequence (SEQ.ID.NO.:2) of which can be found at GenBank accession no. AJ225028 (see also GenBank accession no. AJ012185), as well as to its mammalian orthologs. The amino acid sequence (SEQ.ID.NO.:4) of the mouse ortholog of gbla is found at GenBank accession no. AF114168. gbla also refers to other GABAB receptor subunits that have minor changes in amino acid sequence from those described in the previous two sentences as long as those other GABAB receptor subunits have substantially the same biological activity as the subunits described in the previous two sentences. "gblb" refers to the human GABAB receptor subunit known as GABAβRlb in Kaupmann et al., 1998, Proc. Natl. Acad. Sci. USA 95:14991-14996, the amino acid sequence (SEQ.JJD.NO.:6) of which can be found at GenBank accession no. AJ225029, as well as to its mammalian orthologs. gblb also refers to other GABAβ receptor subunits that have minor changes in amino acid sequence from those described in the previous sentence as long as those other GABAB receptor subunits have substantially the same biological activity as the subunits described in the previous sentence. "gblc" refers to a human GABAB receptor subunit having the amino acid sequence SEQ.ID.NO.:8, encoded by DNA having the nucleotide sequence SEQ.JX).NO.:7, as well as to its mammalian orthologs. The GenBank accession no. for human gblc is AJ012187. gblc also refers to other GABAB receptor subunits that have minor changes in amino acid sequence from those described in the previous two sentences as long as those other GABAB receptor subunits have substantially the same biological activity as the subunits described in the previous two sentences. "gb2" refers to a human GABAB receptor subunit having the amino acid sequence SEQ.ID.NO.:9 encoded by DNA having the nucleotide sequence SEQ.JJD.NO.:10, as well as to its mammalian orthologs. The amino acid sequence of the rat ortholog of gb2 is found at GenBank accession no. AF058795. gb2 also refers to other GAB Aβ receptor gb2 subunits that have minor changes in amino acid sequence from those described in the previous two sentences as long as those other GABAβ receptor subunits have substantially the same biological activity as the subunits described in the previous two sentences. For example, Clark et al., 2000, Brain Res. 860:41-52 disclosed two additional gb2 c-terminal variants in the rat. A human gb2 sequence is also found at GenBank accession no. AF056085. "gbla heteromer" refers to a GABAβ receptor that comprises a gbla subunit and a gb2 subunit and does not comprise a gblb or gblc subunit. Preferably, the gbla heteromer is a heterodimer of a gbla subunit and a gb2 subunit. "gblb heteromer" refers to a GABAB receptor that comprises a gblb subunit and a gb2 subunit and does not comprise a gbla or gblc subunit. Preferably, the gblb heteromer is a heterodimer of a gblb subunit and a gb2 subunit. "gblc heteromer" refers to a GABAB receptor that comprises a gblc subunit and a gb2 subunit and does not comprise a gbla or gblb subunit. Preferably, the gblc heteromer is a heterodimer of a gblc subunit and a gb2 subunit. "gbla cells" refers to cells that express gbla heteromers but not gblb or gblc heteromers; "gblb cells" refers to cells that express gblb heteromers but not gbla or gblc heteromers; "gblc cells" refers to cells that express gblc heteromers but not gbla or gblb heteromers; A gb2 polypeptide has "substantially the same biological activity" as native gb2 (i.e., SEQ. ID. NO.: 10) if that polypeptide has an amino acid sequence that is at least about 80% identical to, preferably at least about 95% identical to, more preferably at least about 97% identical to, and most preferably at least about 99% identical to SEQ.ID.NO.:10 and can form heteromers with either a gbla, gblb, or gblc polypeptide, thus forming a functional GABAB receptor. "Functional GABAB receptor" refers to a GABAB receptor formed by co-expression of gb2 and gbla, gblb, or gblc, most preferably resulting in a heterodimer of gb2 and either gbla, gblb, or gblc, where the functional GABAB receptor mediates at least one functional response when exposed to the GABAB receptor agonist GABA. Examples of functional responses are: pigment aggregation in Xenopus melanophores, negative modulation of cAMP levels, coupling to inwardly rectifying potassium channels, mediation of late inhibitory postsynaptic potentials in neurons, increases in potassium conductance, decreases in calcium conductance, MAPKinase activation, extracellular pH acidification, and other functional responses typical of G-protein coupled receptors. One skilled in the art would be familiar with a variety of methods of measuring the functional responses of G-protein coupled receptors such as the GABAβ receptor (see, e.g., Lerner, 1994, Trends Neurosci. 17:142-146 [changes in pigment distribution in melanophore cells]; Yokomizo et al., 1997, Nature 387:620-624 [changes in cAMP or calcium concentration; chemotaxis]; Howard et al., 1996, Science 273:974-977 [changes in membrane currents in Xenopus oocytes]; McKee et al., 1997, Mol. Endocrinol. 11:415-423 [changes in calcium concentration measured using the aequorin assay]; Offermanns & Simon, 1995, J. Biol. Chem. 270:15175-15180 [changes in inositol phosphate levels]). Depending upon the cells in which heteromers of gb2 and either gbla, gblb, or gblc are expressed, and thus the G-proteins with which the functional GABAβ receptor thus formed is coupled, certain of such methods may be appropriate for measuring the functional responses of such functional GAB Aβ receptors. It is well within the competence of one skilled in the art to select the appropriate method of measuring functional responses for a given experimental system. A gbla polypeptide has "substantially the same biological activity" as a native gbla polypeptide if that polypeptide has an amino acid sequence that is at least about 80% identical to, preferably at least about 95% identical to, more preferably at least about 97% identical to, and most preferably at least about 99% identical to SEQ.ID.NO.:2 and either (1) has a K or EC50 for an amino acid (in particular neutral and branched chain amino acids, including leucine, isoleucine, valine), amino acid analogue (such as γ-hydroxybutyrate or phosphinic acids), GABAB receptor agonist (such as (R,S)baclofen, gabapentin or similar 3-liphophilic substituted GABA analogues, or (L)-glutamic acid), or GABAB receptor antagonist (such as CGP71872, saclofen, or phaclofen), that is no more than 5-fold greater than the K or EC50 of a native gbla polypeptide for the same amino acid, amino acid analogue, GABAB receptor agonist, or GABAB receptor antagonist or (2) can form heteromers with a gb2 polypeptide, thus forming a functional GABAB receptor. Native gbla polypeptides include the murine gbla sequence shown as SEQ.JX>.NO.:4; the rat gbla polypeptide disclosed in Kaupmann et al., 1997, Nature 386:239-246; the human gbla sequence disclosed in GenBank accession number AJ225028 (SEQ.ID.NO.:2); and the protein encoded by the DNA sequence disclosed in GenBank accession number Y11044. A gblb polypeptide has "substantially the same biological activity" as a native gblb polypeptide if that polypeptide has an amino acid sequence that is at least about 80% identical to, preferably at least about 95% identical to, more preferably at least about 97% identical to, and most preferably at least about 99% identical to SEQ.JX).NO.:6 and either (1) has a Kd or EC50 for an amino acid (in particular neutral and branched chain amino acids, including leucine, isoleucine, valine), amino acid analogue (such as γ-hydroxybutyrate or phosphinic acids), GABAβ receptor agonist (such as (R,S)baclofen, gabapentin or similar 3-liphophilic substituted GABA analogues, or (L)-glutamic acid), or GABAB receptor antagonist (such as CGP71872, saclofen, or phaclofen), that is no more than 5-fold greater than the Kd or EC50 of a native gblb polypeptide for the same amino acid, amino acid analogue, GAB Aβ receptor agonist, or GAB Aβ receptor antagonist or (2) can form heteromers with a gb2 polypeptide, thus forming a functional GABAB receptor. Native gblb polypeptides include the human gblb sequence disclosed in GenBank accession number AJ225029 (SEQ.ID.NO.:6) and the rat gblb polypeptide disclosed in Kaupmann et al., 1997, Nature 386:239-246. A gblc polypeptide has "substantially the same biological activity" as a native gblc polypeptide if that polypeptide has an amino acid sequence that is at least about 80% identical to, preferably at least about 95% identical to, more preferably at least about 97% identical to, and most preferably at least about 99% identical to SEQ.ID.NO.:8 and either (1) has a K or EC50 for an amino acid (in particular neutral and branched chain amino acids, including leucine, isoleucine, valine), amino acid analogue (such as γ-hydroxybutyrate or phosphinic acids), GABAβ receptor agonist (such as (R,S)baclofen, gabapentin or similar 3-liphophilic substituted GABA analogues, or (L)-glutamic acid), or GABAB receptor antagonist (such as CGP71872, saclofen, or phaclofen), that is no more than 5-fold greater than the Kd or EC50 of a native gblc polypeptide for the same amino acid, amino acid analogue, GAB Aβ receptor agonist, or GAB Aβ receptor antagonist or (2) can form heteromers with a gb2 polypeptide, thus forming a functional GABAβ receptor. Native gblc polypeptides include the amino acid sequence shown as SEQ.JJO.NO.:8. A substance "activates a functional response" by interacting with functional GABAβ receptors on the surface of cells when the cells are exposed to the substance, leading to an increase in the level of the functional response. For example, if the functional response is the activation of a Kir channel, then a substance that activates a "functional response" of a GAB Aβ receptor is a substance that acts as an agonist at the GABAβ receptor so as to cause increased potassium ion flow through the Kir channel. A "conservative amino acid substitution" refers to the replacement of one amino acid residue by another, chemically similar, amino acid residue. Examples of such conservative substitutions are: substitution of one hydrophobic residue (isoleucine, leucine, valine, or methionine) for another; substitution of one polar residue for another polar residue of the same charge (e.g., arginine for lysine; glutamic acid for aspartic acid). The present invention provides methods for identifying substances that are subtype-specific agonists of the GABAB receptor. In particular, the substances function as agonists of GABAB receptors that are heteromers of gbla and gb2 subunits. The substances are not agonists of GABAβ receptors that are heteromers of gblb and gb2 subunits; nor are they agonists of GABAβ receptors that are heteromers of gblc and gb2 subunits. In CA1 pyramidal neurons of rat hippocampal slices, the substances activate post-synaptic potassium currents but do not presynaptically depress GABA inhibitory postsynaptic currents. The substances are not agonists of GABAA receptors. The substances are agonists of GABAB receptors that are negatively coupled to voltage dependent-calcium channels in HEK293 cells, melanotroph cell lines derived from mouse intermediary lobe pituitary tumors, and in rat hippocampal neurons or spinal cord neurons. There are currently three known isoforms of the GABAB receptor gbl subunit: gbla, gblb, and gblc. gbla, gblb, and gblc are proteins of 961, 844, and 899 amino acids, respectively, differing only in that portion of their ligand binding extracellular N-termini that precedes a domain that is homologous to the bacterial periplasmic leucine-binding protein (Ng et al., 2001, Mol. Pharm. 59:144-152; Kaupmann et al., 1997, Nature 386:239-246; Galvez et al., 1999, J. Biol. Chem. 274:13362-13369) (Figure 1A). The gbla-specific N-terminal sequence is comprised primarily of two protein-protein interacting Sushi Repeat (also known as short consensus repeat) domains of ~60 amino acids, the first corresponding to T26_R98 and the second to Kl02-Nl60 described by Kaupmann et al., 1998, Proc. Natl. Acad. Sci. USA 95: 14991-14996. gblb differs from gbla in that the first 164 amino acids of gbla are replaced by 47 different amino acids. Thus gblb lacks both N-terminus Sushi Repeats. The gblc isoform differs from gbla by an in-frame 62 amino acid deletion and elimination of one Sushi Repeat, leaving a single Sushi Repeat interacting module. Activation of neuronal GABAg receptors leads to increases in K+ membrane conductance which have been associated with a postsynaptic site (Sodickson & Bean, 1998, J. Neurosci. 18:8153-8162). gbla and gblb have been reported to exhibit differential post and presynaptic localizations, respectively (Benke et al., 1999, J. Biol. Chem. 274:27323-27330; Fritschy et al., 1999, Eur. J. Neurosci. 11 :761-768). These two subunits, as well as the gblc isoform, were tested to determine whether, when expressed as homomers or heteromers with gb2, they could couple with Kir3.1/3.2 in Xenopus oocytes, an established model for studying GPCR- activated inward rectifiers (Kir channels; Dascal, 1997, Cell Signal. 9:551-573). Human or murine gbla, human gblb, and human gblc isoforms are inactive when expressed individually (data not shown). All three gbl isoforms require co- expression with gb2 in order to form structurally distinct, functional GABAB receptors that can couple to Kir 3.1/3.2 channels and that are activated by GABA (Figure 2). However, gabapentin (100 μM) could only activate Kir 3.1/3.2 channels through the gbla heteromer (Figure 2). Co-expression of human gbla and gb2 with Kir 3.1/3.2 in Xenopus oocytes resulted in a significant stimulation of Kir current in response to 100 μM GABA (297 +/- 30.5% increase over control current measured at -80 mV, n=6). This was confirmed at the murine gbla heteromer (290 +/- 40% increase over control current measured at -80 mV, n=6), and maximal stimulation was similar with the human gbla heteromer. Gabapentin agonism at the gbla heteromer could be blocked by 1 μM CGP71872, a GABAB antagonist (data not shown). In contrast to the results obtained with gbla heteromers, no response to gabapentin was detected (n=6) after stimulation of gblb (n=9) or gblc (n=4) heteromers, although GABA-mediated responses were always detected in the same oocytes (Figure 2, ' Figure 3A). This demonstrates a gbla subtype-specific effect of gabapentin. Another difference between the responses to GABA and gabapentin was manifested by the rapid and consistent desensitization of the response to gabapentin during its continual presence (Figure 2), essentially resulting in a return to basal current levels during 1 minute of stimulation. A markedly reduced desensitization was occasionally detectable in responses to GABA (Figure 2) or baclofen (data not shown). As for stimulation of GABAB receptors by GABA, only modest desensitization of current was detected during stimulation by M2- or β2AR agonists (Figure 2), consistent with reports in the literature using the oocyte expression system (Doupnik et al., 1997, Proc. Natl. Acad. Sci. USA 94:10461- 10466; Fidler-Lim et al., 1995, J. Gen. Physiol. 105:421-439). Studies of dose dependency at gbla heteromers revealed a rank order of potency: GABA > baclofen > gabapentin with EC50 values of 1.1, 1.9, and 19 μM, respectively (Figure 3B). Consistent with the potency of GABA in this assay, synaptic concentrations of GABA have been reported to reach up to 5 μM (Mody et al., 1994, Trends. Neurosci. 17:517-525). The approximately 20 μM potency of gabapentin at the gbla heteromer is also consistent with its therapeutic dose as monotherapy in the treatment of epilepsy or neuropathy (10-100 μM in brain following dosing up to 3.6 g/day) (Bryans & Wustrow, 1999, Med. Res. Rev. 19:149- 177; Backonja et al., 1998, J. Am. Med. Assn. 280:1831-1836; Rowbotham et al., 1998, J. Am. Med. Assn. 280:1837-1842). This suggests that one mechanism by which gabapentin exerts its therapeutic action is through gbla subtype-specific GABAβ receptor agonism. Gabapentin and baclofen at 10 μM final concentration inhibited [3H]TBOB specific binding to rat brain cortex GABAA chloride channel site by 18% and 5%, respectively. However, gabapentin was inactive (up to 100 μM) in functional assays at recombinant GABA^ receptors (data not shown). Gabapentin and baclofen displaced specific [3H]GABA binding at rat cerebellum GABAg receptors by 24-26% and 22%, respectively, suggesting that gabapentin, like baclofen, interacts with neuronal GABA β receptors. Gabapentin was tested to determine if it was active at native GABAg receptors in CA1 pyramidal neurons of rat hippocampal slices (Luscher et al., 1997, Neuron 19:687-695) (Figure 4; see Example 4 for experimental details). Currents evoked by bath application of baclofen and gabapentin were isolated using voltage ramps and a subtraction procedure during whole cell patch clamp recordings (Nurse & Lacaille, 1999, Neuropharmacol. 38:1733-1742). Whole cell membrane currents were measured during voltage ramps from -40 to -140 mV. Currents obtained from the I-V relation in control ACSF were subtracted from those in the presence of either baclofen or gabapentin (Figure 4B) to isolate drug-activated currents. The current- voltage relation for these currents indicated that 1 mM gabapentin activated outward currents at membrane potentials near rest (Figure 4B). These gabapentin currents reversed and became inward near -100 mV (mean E re v = -101.0 ± 2.2 mV, n = 7 cells), which is near the equilibrium potential for K+ in this preparation. These results indicate that gabapentin activated potassium currents in CA1 pyramidal neurons. Gabapentin currents were dose-dependent, their mean chord conductance increasing with doses between 0.01-1 mM (Figure 4B and 4D). Bath application of 2- 20 μM (-)baclofen elicited similar potassium currents that were outward at membrane potentials near rest, reversed near -100 mV (mean E r ev = -101.5 ± 2.6 mV, n = 6 cells), and were dose-dependent (Figure 4C and 4D). Potassium currents activated by 1 mM gabapentin and 20 μM baclofen were coupled to GAB Aβ receptors since they were reduced by 89% and 84%, respectively, by pretreatment with the GABAB receptor antagonist CGP55845 (4 and 1 μM respectively, Figure 4D). These results indicate that gabapentin activated potassium currents linked to postsynaptic GABAB receptors in CA1 pyramidal cells and these actions of gabapentin were similar to the postsynaptic actions of baclofen. Since neuronal GABAβ receptors are also located presynaptically and such presynaptic GAB Aβ receptors are coupled to inhibition of transmitter release (Bowery, 1993, Ann. Rev. Pharmacol. Toxicol. 33 : 109-147), it was of interest to assess whether gabapentin activated presyntaptic GABAB receptors that inhibit GABA release in hippocampal neurons in situ (Davies et al., 1990, J. Physiol (London) 424:513-531; Thompson, 1994, Prog. Neurobiol. 42:575-609). Fast monosynaptic GABA inhibitory postsynaptic currents (IPSCs) were evoked in CA1 pyramidal cells by electrical stimulation of stratum radiatum in the presence of blockers of glutamate synaptic transmission (antagonists of non-NMDA and NMDA glutamate receptors, CNQX and AP5, respectively) (Figure 5A). These fast outward IPSCs recorded near resting membrane potential were mediated by GABAA receptors since they were completely antagonized by 25 μM bicuculline (n=l 1 cells, data not shown). Fast GABAA IPSCS were reversibly reduced by 75% by bath application of 20 μM baclofen (Figure 5B). This presynaptic inhibition by baclofen was dose- dependent (2-20 μM) and was antagonized by the GAB Aβ receptor antagonist CGP55845 (1 μM; Figure 5D). In contrast, gabapentin (0.01-1 mM) did not significantly depress GABAA IPSCS (Figure 5C and 5D), even during bath applications that elicited outward currents in the same cells (not shown). The small and variable reduction in IPSC amplitude observed in the presence of gabapentin (6- 13%) was not significantly different from the reduction observed during repeated application of control ACSF (7%) or after pretreatment with the GABAβ antagonist GP55845 (16%) (Figure 5D). This minor reduction therefore does not result from gabapentin effects. These results indicate that whereas baclofen activated presynaptic GABAB receptors and inhibited GABA release, gabapentin did not. Thus gabapentin does not have presynaptic actions like baclofen in CA1 hippocampus. Furthermore, gabapentin was inactive up to 100 μM in functional assays at the recombinant GABAA αlβ3γ2, α3β3γ2, and α4β3γ2 receptor subtypes (data not shown). Gabapentin was also inactive up to 100 μM in functional assays at the recombinant NMDA NR2B receptor (data not shown). In addition, further studies with gabapentin demonstrated that GABAB receptors are negatively coupled to voltage-dependent calcium channels (VD-CCs ) in rat hippocampal neurons. During combined whole cell recording and multiphoton Ca2+ imaging in hippocampal neurons in situ, gabapentin significantly inhibited, in a dose-dependent manner, subthreshold soma depolarizations and Ca2+ responses evoked by somatic current injection. Further, gabapentin almost completely blocked Ca2+ action potentials and Ca2+ responses elicited by suprathreshold current injection. However, larger current injection overcame this inhibition of Ca2+ action potentials, suggesting that gabapentin did not predominantly affect L-type Ca2+ channels. The depressant effect of gabapentin on Ca2+ responses was coupled to the activation of neuronal GAB Aβ receptors since they were blocked by CGP55845, and baclofen produced similar effects. Thus, gabapentin activation of neuronal gbla heteromers negatively coupled to VD-CCs is potentially an important therapeutic mechanism of action of gabapentin, which may be linked to inhibition of neurotransmitter release in some systems. The results disclosed herein further indicate that gabapentin may have multiple anticonvulsant actions linked to GABAβ receptors. In addition to its selective activation of gbla heteromers coupled to GIRKs that produce postsynaptic hyperpolarization, gabapentin may inhibit Ca2+ influx during burst discharges or seizures via its activation of postsynaptic gbla heteromers negatively coupled to VD- CCs. It is interesting to note that gabapentin actions on hippocampal neurons are therefore dictated not only by its selective activity at the gbla heteromer subtype, but also by the cellular domain where these receptors are found in the cell. Gabapentin- sensitive GAB Aβ receptors present in the soma and dendritic regions couple to VD- CCs (Figures 15-17) and GIRKs (Figure 4). In contrast, the gblb and gblc heteromer subtypes, which are likely present in glutamate and GABA axon terminals of hippocampal neurons and also are negatively coupled to VD-CCs, are insensitive to gabapentin. This is in agreement with the subtype selective agonist activity defined using recombinant receptors (Figures 2 and 3) and the lack of presynaptic effect of gabapentin on synaptic transmission in hippocampus (Figure 5). Gabapentin has been recently reported to depress excitatory amino acid neurotransmission in spinal cord dorsal horn (Patel et al., 2000, British J Pharmacol. 130: 1731-1734; Shimoyama et al., 2000, Pain 85:405-414), and the effect of the agonist gabapentin on GABAβ receptors coupled to VD-CCs could account for these effects since a well established physiological role of presynaptic neuronal GABAβ receptors is inhibition of P/Q and N-type VD-CCs and transmitter release (Bowery & Enna, 2000, J. Pharmacol. Exp. Ther. 292:2-7; Wu & Saggau, 1997, Trends Neurosci. 20:204-212; Menon- Johansson et al., 1993, Pflugers Arch. 425:335- 343). This conclusion is also consistent with the anatomical localization of the gbla heteromer to some presynaptic elements in the neural axis (Benke et al., 1999, J. Biol. Chem. 274:27323-27330; Billinton et al., 1999, Br. J. Pharmacol. 126:1387-1392; Towers et al, 2000, Eur. J. Neurosci. 12:3201-3210). GABAB receptor distribution studies in the lumbar spinal cord and dorsal root ganglia showed that the gbla mRNA is the predominant species (accounting for ~90%) of the total gbl mRNA in the afferent fiber cell body. This suggests that gbla subunits together with gb2, which exhibit equivalent density to gbla, comprise presynaptic GABAβ receptors on primary afferent terminals (Towers et al., 2000, Eur. J. Neurosci. 12:3201-3210). Indeed, in this report, immunocytochemical analysis showed denser labeling of gbla in the superficial dorsal horn and present in neuropil whereas gblb was more associated with cell bodies in this region. The predominant expression of gbla heteromers in the superficial laminae where nociceptive primary afferent fibers terminate, together with studies which suggests the anti-nociceptive effects of baclofen (Hammond & Drower, 1984, Eur. J. Pharmacol. 103:121-125; Sawynok & Dickson, 1985, Pharmacology 31:248- 259; Henry, 1982, Neuropharmacology 21:1085-1093) and gabapentin (Xiao & Bennet, 1996, Analgesia 2:267-273; Patel et al., 2000, Br. J. Pharmacol. 130:1731- 1734; Shimoyama et al., 2000, Pain 85:405-414) are mediated presynaptically, suggest that, at least in part, the anti-hyperalgesic, anti-allodynic and anti-nociceptive effects of gabapentin can be attributed to selective activation of presynaptic gbla heteromers coupled to VD-CCs in the spinal cord dorsal horn. Additionally, the selective agonism of presynaptic gbla heteromers in the spinal cord dorsal horn may underlie the efficacy of GABAB agonists such as baclofen in the treatment of urinary incontinence. A structural basis for the pharmacological difference among GABAg receptor subtypes likely owes to gb la-specific sequences which comprise primarily a Sushi repeat (Kl02_Nl60) which is absent in the gblb and gblc subunits. A recent model has been proposed which suggests that agonist binding at GABAg receptors is similar to bacterial periplasmic amino acid binding proteins where the extracellular domain folds into two lobes separated by a hinge region (Galvez et al., 1999, J. Biol. Chem. 274:13362-13369). It may be that the gbla-specific Sushi domain modulates the closure of this "Venus Flytrap"-like domain such that it can bind gabapentin while other gbl receptor subtypes cannot. Another possible explanation for the pharmacological difference among GABAg receptor subtypes would be the existence of an additional protein or proteins from the cellular environment which may also be required for gabapentin activity at GABAB receptors. Such a requirement would be analogous to the case of the CGRP receptor where CRLR and RAMPs are required for the functional CGRP receptor. This accessory protein or proteins would be present in a gabapentin-sensitive GAB Aβ receptor expressing cells but not in gabapentin-insensitive GABAβ receptor expressing cells. GABA inhibition in the CNS involves multiple mechanisms. These include fast postsynaptic inhibition via activation of GABAA receptor chloride channels, slow postsynaptic inhibition via activation of GABAB receptors and G- protein-regulated inward rectifying potassium channels, and presynaptic inhibition via negative modulation of Ca2+ channels in presynaptic terminals, reducing glutamate and GABA release (Nicoll et al., 1990, Physiol. Rev. 70:513-565; Sivilotti et al., 1991, Prog. Neurobiol. 36:35-92; Thompson et al., 1994, Prog. Neurol. 42:575-609). Fast postsynaptic GABAA responses result from activity at single synapses, whereas slower GABAB responses necessitate the synchronous activation of multiple presynaptic fibers (Dutar et al., 1988, Nature 332:156-158; Otis et al., 1992, J. Neurophysiol. 67:227-235). In addition, postsynaptic GABAB receptors appear important for curtailing epileptiform activity in the presence of impaired GABAA inhibition (Malouf et al., 1990, Neuroscience 35:53-61; Scanziani et al., 1991, J. Physiol. (London) 444:375-396). In hippocampal neurons, postsynaptic GABAB receptor activation leads to membrane hyperpolarization, mediated by inward rectifying potassium channels (Luscher et al., 1997, Neuron 19:687-695). Further, subcellular localization studies show that gbla is predominantly postsynaptic whereas gblb is largely presynaptic (Benke et al., 1999. J. Biol. Chem. 274:27323-27330; Fritschy et al., 1999, Eur. J. Neurosci. 11:761-769) although one study concludes differently (Billinton et al, 1999, Br. J. Pharmacol. 126:1387-1392). The present data show for the first time that gabapentin is a GABAB gbla heteromer subtype-specific agonist and is selective for postsynaptic GABAB receptors in hippocampus, providing the first in situ evidence of structurally and pharmacologically distinct pre- and postsynaptic GABAβ receptor subtypes. The present study thus shows that gabapentin is a member of a class of pharmacological agents that possess a particular combination of characteristics: • they are agonists of GABAB receptors that are heteromers of gbla and gb2 subunits • they are not agonists of GABAβ receptors that are heteromers of gblb and gb2 subunits • they are not agonists of GABAB receptors that are heteromers of gblc and gb2 subunits • they activate post-synaptic potassium currents • they do not presynaptically depress GABA inhibitory postsynaptic currents • they are not agonists of GABAA receptors • they exhibit rapid desensitization and a distinct mechanism of activation compared to baclofen at the coupled receptor • they are agonists of GABAβ receptors that are negatively coupled to voltage dependent-calcium channels in heterologous expression systems such as HEK-293 cells, melanotroph cell lines derived from mouse intermediary lobe pituitary tumors and in rat hippocampal neurons, dorsal root ganglion neurons, and spinal cord dorsal horn neurons It is likely that this combination of characteristics, or some subset of this combination, is responsible for the therapeutic effectiveness of gabapentin. Therefore, it would be of great interest to identify other substances that share this combination of characteristics, or some subset of this combination. The present invention provides methods for identifying such substances. The present invention provides methods of identifying gbla subtype- specific agonists of the GABAB receptor that comprise (a) determining that a substance is an agonist of GABAB receptors comprising a gbla subunit; and (b) determining that the substance is not an agonist of GAB Aβreceptors comprising a gb 1 b or gb 1 c subunit. Optionally, the methods comprise determining that the substance activates post-synaptic potassium currents but does not presynaptically depress GABA inhibitory postsynaptic currents. The methods also optionally include determining that the substance is not an agonist of GABAA receptors and/or determining that the substances are agonists of GABAβ receptors that are negatively coupled to voltage dependent-calcium channels in heterologous expression systems such as HEK-293 cells, melanotroph cell lines derived from mouse intermediary lobe pituitary tumors, and in rat hippocampal neurons, dorsal root ganglion neurons and spinal cord dorsal horn neurons. One method of identifying substances that are likely to be gbla subtype-specific agonists is to identify those substances that are capable of binding to gbla heteromers but that are not also capable of binding to gblb or gblc heteromers. This can be done by screening a collection of compounds against three types of cells, with each type of cell expressing either a gbla, gblb, or gblc heteromer and determining the amount of each compound that binds to each type of cell. Those compounds for which at least 3 times, preferably at least 10 times, and even more preferably at least 50 times more compound is bound to cells expressing the gbla heteromer (as compared to cells expressing either gblb or gblc heteromers) are likely to be gbla subtype-specific agonists. Of course, one would go on to test such compounds in the functional assays that are described herein to make sure that they are indeed agonists rather than antagonists or compounds that simply bind without affecting function. Accordingly, the present invention includes a method of identifying a substance that is a gbla subtype-specific agonist comprising: (a) exposing a substance, separately, to gbla cells, gblb cells, and gblc cells; (b) quantitating the binding of the substance to the gbla cells, gblb cells, and gblc cells; where, if the amount of binding of the substance to the gbla cells is at least 3 times greater than the amount of binding of the substance to either gblb or gblc cells, then; (c) determining whether the substance activates a functional response of a gbla heteromer; where if the substance activates a functional response of a gbla heteromer then the substance is a gbla subtype-specific agonist. The identification of gbla subtype-specific agonists can be facilitated by the use of gabapentin. New gbla subtype-specific agonists are likely to be able to compete with gabapentin for binding to gbla heteromers. This allows for the development of assays to identify gbla subtype-specific agonists based on such competition. Moreover, pregabalin ((S)-3-isobutylgaba) is a compound that is structurally related to gabapentin and has been found to inhibit the binding of [3H] gabapentin to brain membranes (Taylor et al, 1993, Epilepsy Res. 14:11-15) as well as to have similar pain relieving effects in animal models (Field et al., 1999, Pain 80:391-398). In view of this similarity between the two compounds, it is within the scope of the present invention to utilize pregabalin instead of gabapentin in certain embodiments of the invention. Also, within the scope of the invention is the utilization of other 3 'substituted GABA analogues. Accordingly, the present invention includes a method for identifying gbla subtype-specific agonists that comprises: (a) providing gbla cells; (b) exposing the gbla cells to gabapentin or pregabalin in the presence and in the absence of a substance; (c) measuring the binding of gabapentin or pregabalin to the gbla cells in the presence and in the absence of the substance; where, if the amount of binding of gabapentin or pregabalin is less in the presence of the substance than in the absence of the substance, then; (d) determining whether the substance binds to gblb cells and gblc cells; where, if the substance does not bind to gblb cells and gblc cells, then; (e) determining whether the substance activates a functional response of a gbla receptor; where if the substance activates a functional response of a gbla receptor then the substance is a gbla subtype-specific agonist. The skilled person will recognize that it is generally beneficial to run controls at various points in the methods described herein. For example, in the method described immediately above, it will usually be helpful to have a control for step (c) in which the binding of gabapentin or pregabalin to the cells is shown to be dependent on the presence of gbla heteromers. This can be done by measuring the binding of gabapentin or pregabalin to cells that are substantially the same as the cells of step (c) except for the lack of gbla heteromers. One way to do this is to use cells that recombinantly express gbla heteromers. The non-recombinant parent cells would then serve as controls. Another control would be to take the substances identified by the methods described herein and confirm that the substances do not activate a functional response at GABAβ receptors that are gblb heteromers or gblc heteromers. One skilled in the art would also recognize that the phrase "does not bind to" in the methods described herein has a relative meaning. This phrase does not exclude some low level, insignificant binding that is non-specific, i.e., that is not due to the presence of gblb or gblc. Such non-specific binding can be assessed by running various controls. This phrase may even apply to situations where the substance does bind to gblb or gblc, but at an insignificant amount as compared to its binding to gbla. In this context, an insignificant amount would be, e.g., 5%, 1%, or 0.1% or less. The present invention includes a method of identifying a substance that is a gbla subtype-specific agonist comprising: (a) providing cells expressing gbla but not gblb or gblc; (b) exposing the cells of step (a) to a substance; (c) quantitating the binding of the substance to the cells of step (a); (d) providing cells expressing gblb but not gbla or gblc; (e) exposing the cells of step (d) to the substance; (f) quantitating the binding of the substance to the cells of step (d); (g) providing cells expressing gblc but not gbla or gblb; (h) exposing the cells of step (g) to the substance; (i) quantitating the binding of the substance to the cells of step (g); where, if the amount of binding of the substance to the cells of step (a) is at least 3 times greater than the amount of binding of the substance to the cells of step (d) and the cells of step (g), then; (j) determining whether the substance activates a functional response of a gbla heteromer; where if the substance activates a functional response of a gbla heteromer then the substance is a gbla subtype-specific agonist. The cells of steps (a), (d), and (g) should be substantially identical except for their differences in expression of gbla, gblb, and gblc. One method of obtaining such cells is to recombinantly express gbla, gblb, or gblc in a cell line that does not naturally express gbla, gblb, or gblc. Preferred embodiments of the methods described herein make use of recombinant cells containing expression vectors that direct the expression of the various GAB Aβ receptor subunits. Thus, the present invention includes a method for identifying gbla subtype-specific agonists that comprises: (a) providing cells comprising an expression vector encoding gb2 and an expression vector encoding gbla; (b) culturing the cells under conditions such that gb2 and gbla are expressed and gbla heteromers are formed; (c) exposing the cells to gabapentin or pregabalin in the presence and in the absence of a substance; (d) measuring the binding of gabapentin or pregabalin to the gbla heteromers in the presence and in the absence of the substance; where if the amount of binding of gabapentin or pregabalin is less in the presence of the substance than in the absence of the substance, then; (e) determining whether the substance binds to gblb cells and gblc cells; where, if the substance does not bind to gblb cells and gblc cells, then; (f) determining whether the substance activates a functional response of a gbla heteromer; where if the substance activates a functional response of a gbla heteromer then the substance is a gbla subtype-specific agonist. The gblb cells and gblc cells of step (e) should be substantially identical to each other as well as to the cells of step (a) except for the differences in expression of gbla, gblb, and gblc in the three types of cells. One method of producing such cells is to begin with a parental cell line that does not express either gbla, gblb, or gblc and to separately transfect expression vectors encoding gbla, gblb, and gblc into the parental cells, thereby producing three cell lines, each cell line expressing only one of gbla, gblb, and gblc. One skilled in the art would recognize that the phrase "where if the amount of binding of gabapentin or pregabalin is less in the presence of the substance than in the absence of the substance" in the methods described herein has a relative, not an absolute, meaning. Substances of interest identified by the methods described herein cause the binding of gabapentin or pregabalin to be less in a non-trivial manner. Such substances would, e.g., decrease the binding of gabapentin or pregabalin by at least about 50%, preferably by about 75%, more preferably by about 95%, and even more preferably by about 99%. One skilled in the art would understand that when practicing such competition assays as those described herein, it is important that the relative amounts of the various compounds and substances used be appropriate. For example, in the method described immediately above, one would not attempt to detect competitive displacement of the binding or gabapentin or pregabalin by the substance by using a vast excess (e.g., a 1,000-fold molar excess) of substance as compared to gabapentin or pregabablin. One would preferably use the substance and the gabapentin or pregabalin at more or less equal molar concentrations. The present invention includes a method for identifying a gbla subtype-specific agonist that comprises: (a) determining whether a substance activates a GABAB receptor functional response in gbla cells; (b) determining whether the substance activates a GABAB receptor functional response in gblb cells; (c) determining whether the substance activates a GABAB receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in gbla cells, but not in gblb or gblc cells, then the substance is a gbla subtype-specific agonist. In particular embodiments of the methods described herein, the functional response is selected from the group consisting of: modulation of the activity of an ion channel; changes in calcium concentration; changes in a signal from a reporter gene whose expression is controlled by a promoter that is induced by interaction of an agonist with the GABAβ receptor; and changes in membrane currents. In particular embodiments, the change in membrane current is measured in Xenopus oocytes. In other embodiments, the change in membrane current is caused by the modulation of the activity of an inwardly rectifying potassium current. . In other embodiments, the change in membrane current is caused by the modulation of the activity of a voltage dependent-calcium channel (VD-CC). It is known that activation of the GAB Aβ receptor inhibits ion flow through VD-CCs (Dolphin, 1995, Exp. Physiol. 80: 1-36; Filippov et al., 2000, J. Neurosci. 20:2867- 2874). Therefore, it is possible to use changes in intracellular calcium levels arising from such inhibition of VD-CCs as a surrogate measure of the activity of agonists at the GABAB receptor. When the functional response is a change in intracellular calcium concentration, such a change can be monitored by the use of appropriate indicator dyes (e.g., fura-2, fluo-3, indo-1, Calcium Green; see Veligelebi et al., 1999, Meth. Enzymol. 294:20-47) and suitable detection instruments. Electrophysiological measures could also be used to detect activity at GABAB receptors coupled to VD- CCs. Indicator dyes are substances which show a change in a fluorescent characteristic upon binding calcium, e.g., greatly increased intensity of fluorescence and/or a change in fluorescent spectra (i.e., a change in emission or excitation maxima). Fluo-3, fura-2, and indo-1 are commonly used calcium indicator dyes that were designed as structural analogs of the highly selective calcium chelators ethylene glycol-bis(β-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) and l,2-bis(2- aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA). The fluorescence intensity from fluo-3 increases by more than 100-fold upon binding of calcium. While the unbound dye exhibits very little fluorescence, calcium-bound fluo-3 shows strong fluorescence emission at 526 nm. Fura-2 is an example of a dye that exhibits a change in its fluorescence spectrum upon calcium binding. In the unbound state, fura-2 has an excitation maximum of 362 nm. This excitation maximum shifts to 335 nm upon calcium binding, although there is no change in emission maximum. Binding of calcium to fura-2 can be monitored by excitation at the two excitation maxima and determining the ration of the amount of fluorescence emission following excitation at 362 nm compared to the amount of fluorescence emission following excitation at 335 nm. A smaller ratio (i.e., less emission following excitation at 362 nm) indicates that more fura-2 is bound to calcium, and thus a higher internal calcium concentration in the cell. The use of calcium indicator dyes entails loading cells with the dye, a process which can be accomplished by exposing cells to the membrane-permeable acetoxymethyl esters of the dyes. Once inside the plasma membrane of the cells, intracellular esterases cleave off the esters, exposing negative charges in the free dyes. This prevents the free dyes from crossing the plasma membrane and thus leaves the free dyes trapped in the cells. Measurements of fluorescence from the dyes are then made, the cells are treated in such a way that the internal calcium concentration is changed (e.g., by exposing gbla cells to a gbla subtype-specific agonist), and fluorescence measurements are again taken. Fluorescence from the indicator dyes can be measured with a luminometer or a fluorescence imager. One preferred detection instrument is the Fluorometric Imaging Plate Reader (FLIPR) (Molecular Devices, Sunnyvale, CA). The FLIPR is well suited to high throughput screening using the methods of the present invention as it incorporates integrated liquid handling capable of simultaneously pipetting to 96 or 384 wells of a microtiter plate and rapid kinetic detection using a argon laser coupled to a charge-coupled device imaging camera. Using this approach, it may be desirable to engineer the cells employed so as to recombinantly express calcium channels that are coupled to the GABAB receptor as well as promiscuous G-proteins. A typical protocol for use of calcium indicator dyes would entail plating gbla, gblb, and gblc cells into clear, flat-bottom, black-wall 96 well plates (e.g., those made by Costar or Vue-plates from Packard) and allowing the cells to grow overnight in standard tissue culture conditions (e.g., 5% CO2, 37°C). The cells are generally plated at a density of about 10,000 to 100,000 cells per well in appropriate growth medium. On the day of the assay, growth medium is removed and dye loading medium is added to the wells. If the calcium indicator dye is fluo-3, e.g., dye loading medium could be prepared by solubilizing 50 μg of fluo-3-AM ester (Molecular Probes F-1242) in 22 μl DMSO to give a 2 mM dye stock. Immediately before loading the cells, 22 μl 20% pluronic acid (Molecular Probes P-3000) is added to the dye. The tube containing the dye is mixed with a vortex mixer and 42 ml of the dye/pluronic acid solution is added to 10.5 ml of Hanks Balanced Salt Solution (Gibco/BRL Cat # 14025-076) with 20 mM HEPES (Gibco/BRL Cat # 1560-080), 2.5 mM probenecid (Sigma Cat # P-8761), and 1% fetal bovine serum (Gibco/BRL Cat # 26140-087; not BSA)). The dye and the loading medium are mixed by repeated inversion (final dye concentration about 4 μM). Growth medium can be removed from the cells by washing with the Denley Cellwash (wash medium is Hanks Balanced Salt Solution (Gibco/BRL Cat # 14025-076) with 20 mM HEPES (Gibco/BRL Cat # 1560-080), 2.5 mM probenecid (Sigma Cat # P-8761), and 0.1% bovine serum albumin (Sigma Cat # A-9647; not FBS) three times at volume setting "F" and one last time at volume setting "0," leaving 100 μl residual medium in the wells after the fourth wash. Then 100 μl of the dye in the loading medium is added to each well with a 12 channel pipetter. The cell plate is placed back in the CO2 incubator to load for 60 minutes. Following dye loading, fluorescent measurements of the cells are taken prior to exposure of the cells to substances that are to be tested for gbla subtype- specific agonist activity. The cells are then exposed to the substances and those substances that cause a change in a fluorescent characteristic of the dye are identified. The measuring instrument can be a fluorescent plate reader such as the FLIPR (Molecular Devices). Substances that cause a change in a fluorescent characteristic in the gbla cells but not in the gblb or gblc cells are gbla subtype-specific agonists. The exact details of the procedure outlined above are meant to be illustrative. One skilled in the art would be able to optimize experimental parameters (cell number, dye concentration, dye, loading time, temperature of incubations, cell washing conditions, and instrument settings) by routine experimentation depending on the particular relevant experimental variables (e.g., type of cell used, identity of dye used). Several examples of experimental protocols that can be used are described in Velicelebi et al., 1999, Meth. Enzymol. 294:20-47. The present invention provides a method for identifying gbla subtype- specific agonists comprising: (a) providing gbla cells; (b) loading the gbla cells with a calcium indicator dye; (c) measuring a fluorescence characteristic of the calcium indicator dye in the gbla cells in the presence and in the absence of a substance; (d) providing gblb cells; (e) loading the gblb cells with a calcium indicator dye; (f) measuring a fluorescence characteristic of the calcium indicator dye in the gblb cells in the presence and in the absence of the substance; (g) providing gblc cells; (h) loading the gblc cells with a calcium indicator dye; (i) measuring a fluorescence characteristic of the calcium indicator dye in the gblc cells in the presence and in the absence of the substance; where if a change in fluorescent characteristic in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) and step (i) then the substance is a gbla subtype-specific agonist. In particular embodiments, the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green- 1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. In particular embodiments, the change in fluorescent characteristic is an increase in intensity of a fluorescence emission maximum. In other embodiments, the change in fluorescent characteristic is a shift in the wavelength of an absorption maximum. In particular embodiments, the cells naturally express both GABAB receptors and/or calcium channels. In other embodiments, the cells do not naturally express GABAβ receptors and/or calcium channels but instead have been transfected with expression vectors that encoded GAB Aβ receptors and/or calcium channels so that the cells recombinantly express the GABAβ receptors and/or calcium channels. In particular embodiments, the cells have been transfected with an expression vector that encodes one particular gbl isoform, either gbla, gblb, or gblc so that the transfected cells express one of gbla, gblb, or gblc. In certain embodiments, the cells are also transfected with an expression vector that encodes gb2 so that functional heteromers of gb2 and either gbla, gblb, or gblc are formed in the cells. In particular embodiments, the cells have been transfected with an expression vector that encodes a volatge dependent-calcium channel (VD-CC) subunit or subunits. In preferred embodiments, the subunit or subunits form a functional N-type or a P/Q-type VD-CC. N-type or a P/Q-type VD-CCs are composed of an l subunit, an α2δ subunit, and, usually at least one β subunit. Therefore, it may be advantageous to transfect the cells with an expression vector or vectors that encode an N-type or a P/Q-type αl subunit, α2δ subunit, and β subunit. Cell lines expressing VD-CCs and GABAB receptors can be used in the methods of the present invention. VD-CCs are activated by depolarization of the plasma membrane. This depolarization can be brought about by raising the level of extracellular K+ by, e.g., the addition of KC1 to the medium bathing the cells. This addition of KC1 causes activation of the VD-CCs, influx of extracellular Ca2+ into the cells, and a consequent rise in [Ca2+]j. This rise in [Ca2+]i can be measured by the use of suitable calcium indicator dyes. Readings from the indicator dyes are generally taken within the first 10 seconds or so after activation of the VD-CCs since this is the time period when the influx of Ca2+ through the VD-CCs peaks. At later times, [Ca2+]j rises due to the release of Ca2+ from intracellular stores and it is desirable to minimize interference from this release of intracellular Ca2+. DNA encoding VD-CCs for use in constructing expression vectors encoding the VD-CCs can be obtained by methods well known in the art. For example, a cDNA fragment encoding a VD-CC can be isolated from a suitable cDNA library by using the polymerase chain reaction (PCR) employing suitable primer pairs. Such primer pairs can be selected based upon the known DNA sequence of the VD-CC it is desired to obtain. Suitable cDNA libraries can be made from cellular or tissue sources known to contain mRNA encoding the VD-CC. One skilled in the art could use published VD-CC sequences to design PCR primers and published studies of VD-CC expression to select the appropriate sources from which to make cDNA libraries in order to obtain DNA encoding the VD-CC. The following publications may be of use in this regard: U.S. Patent No. 5,874,236 and U.S. Patent No. 5,429,921 describe various αl and β subunits of human voltage-gated calcium channels; U.S. Patent No. 5,407,820 and U.S. Patent No. 5,710,250 describe α2 subunits of human voltage-gated calcium channels; International Patent Publication WO 98/13490 describes a brain- specific P/Q-type human voltage-gated calcium channel. An alternative to the use of calcium indicator dyes such as those discussed above is the use of the aequorin system to monitor GABAB receptor mediated inhibition of VD-CCs. The aequorin system makes use of the protein apoaequorin, which binds to the lipophilic chromophore coelenterazine forming a combination of apoaequorin and coelenterazine that is known as aequorin. Apoaequorin has three calcium binding sites and, upon calcium binding, the apoaequorin portion of aequorin changes its conformation. This change in conformation causes coelenterazine to be oxidized into coelenteramide, CO2, and a photon of blue light (466 nm). This photon can be detected with suitable instrumentation. Since the gene encoding apoaequorin has been cloned (U.S. Patent No. 5,541,309; U.S. Patent No. 5,422,266; U.S. Patent No. 5,744,579; Inouye et al., 1985, Proc. Natl. Acad. Sci. USA 82:3154-3158; Prasher et al., 1985, Biochem. Biophys. Res. Comm. 126: 1259-1268), apoaequorin can be recombinantly expressed in cells in which it is desired to measure the intracellular calcium concentration. Alternatively, existing cells that stably express recombinant apoaequorin can be used. Such cells derived from HEK-293 cells and CHO-K1 cells are described in Button & Brownstein, 1993, Cell Calcium 14:663-671. For example, the HEK293/aeql7 cell line can be used as follows. The HEK293/aeql7 cells are grown in Dulbecco's Modified Medium (DMEM, GIBCO-BRL, Gaithersburg, MD, USA) with 10%) fetal bovine serum (heat inactivated), 1 mM sodium pyruvate, 500 μg/ml Geneticin, 100 μg/ml streptomycin, 100 units/ml penicillin. Expression vectors encoding the desired combination of GABAβ receptor subunits (gbla, gblb, gblc (or rat gbla-le), gb2) as well as the desired calcium channels subunits (α 1A, oc IB, α ic, ot ID, CC IE, α2δ, βi, β2, β3, β4) and perhaps G protein subunits (Gi, G 0 ) can be transfected into the HEK293/aeql7 cells by standard methods in order to express the desired GABAB receptor subunits, calcium channels subunits, and G protein subunits in the HEK293/aeql7 cells. The cells are washed once with DMEM plus 0.1 % fetal bovine serum, and then charged for one hour at 37°C /5% CO2 in DMEM containing 8 μM coelenterazine cp (Molecular Probes, Eugene, OR, USA) and 30 μM glutathione. The cells are then washed once with Versene (GIBCO-BRL, Gaithersburg, MD, USA), detached using Enzyme-free cellissociation buffer (GIBCO-BRL, Gaithersburg, MD, USA), diluted into ECB (Ham's F12 nutrient mixture (GIBCO- BRL) with 0.3 mM CaCl2, 25 mM HEPES, pH7.3, 0.1% fetal bovine serum). The cell suspension is centrifuged at 500 x g for 5 min. The supernatant is removed, and the pellet was is resuspended in 10 ml ECB. The cell density is determined by counting with a hemacytometer and adjusted to 500,000 cells/ml in ECB. The substances to be tested are diluted to the desired concentrations in ECB and aliquoted into assay plates, preferably in triplicate, at 0.1 ml/well. The cell suspension is injected at 0.1 ml/well, read and integrated for a total of 400 readings using a luminometer (Luminoskan Ascent, Labsystems Oy, Helsinki, Finland). Data are analyzed using the software GraphPad Prism Version 3.0 (GraphPad Software, Inc., San Diego, CA, USA). It will be understood by those skilled in the art that the procedure outlined above is a general guide in which the various steps and variables can be modified somewhat to take into account the specific details of the particular experiment that is desired to be run. For example, one could use semisynthetic coelenterazine (Shimomura, 1989, Biochem. J. 261:913-920; Shimomura et al., 1993, Cell Calcium 14:373-378); the time of incubation of the cells with coelenterazine can be varied somewhat; somewhat greater or lesser numbers of cells per well can be used; and so forth. For reviews on the use of aequorin, see Creton et al., 1999, Microscopy Research and Technique 46:390-397; Brini et al., 1995, J. Biol. Chem. 270:9896-9903; Knight & Knight, 1995, Meth. Cell. Biol. 49:201-216. Also of interest may be U.S. Patent No. 5,714,666 which describes methods of measuring intracellular calcium in mammalian cells by the addition of coelenterazine co-factors to mammalian cells that express apoaequorin. Another type of assay provided by the present invention makes use of Xenopus laevis oocytes that have been microinjected with RNA encoding GABAB receptor subunits as well as inwardly rectifying potassium channels (Kirs). The oocytes are voltage clamped and then exposed to substances while membrane currents are monitored. If the substances are agonists of GABAB receptors, changes in potassium ion flow across the oocytes' membranes will be seen as a result of activation of GAB Aβ receptors and coupling of the GAB Aβ receptors to Kirs. If the substances are able to cause altered potassium currents in oocytes that express gbla heteromers but not also in oocytes that express gblb or gblc heteromers, then the substances are gbla subtype-specific agonists. In an alternative embodiment, the GAB Aβ receptor subunits and the Kirs are expressed in the oocytes by means of an oocytes expression vector (e.g., PT7TS) rather than by microinjection. Accordingly, the present invention includes a method for identifying a gbla subtype-specific agonist of the GABAB receptor comprising: (a) providing a Xenopus laevis oocyte expressing gbla and gb2 so as to form a functional gbla heteromer in the oocyte where the oocyte also expresses a Kir; (b) exposing the oocyte of step (a) to a substance while monitoring potassium ion flow across the oocyte membrane; (c) providing a Xenopus laevis oocyte expressing gblb and gb2 so as to form a functional gblb heteromer in the oocyte where the oocyte also expresses a Kir; (d) exposing the oocyte of step (c) to the substance while monitoring potassium ion flow across the oocyte membrane; (e) providing a Xenopus laevis oocyte expressing gblc and gb2 so as to form a functional gblc heteromer in the oocyte where the oocyte also expresses a Kir; (f) exposing the oocyte of step (e) to the substance while monitoring potassium ion flow across the oocyte membrane; where if the exposure of the oocytes to the substance results in increased potassium ion flow in step (b), but not in steps (d) and (f), then the substance is a gbla subtype-specific agonist of the GABAβ receptor. Particular types of functional assays that can be used to identify gbla subtype-specific agonists include transcription-based assays. Transcription-based assays involve the use of a reporter gene whose transcription is driven by an inducible promoter whose activity is regulated by a particular intracellular event such as, e.g., changes in intracellular calcium levels, that are caused by the interaction of a receptor with a ligand. Transcription-based assays are reviewed in Rutter et al., 1998, Chemistry & Biology 5:R285-R290. Transcription-based assays of the present invention rely on the expression of reporter genes whose transcription is activated or repressed as a result of intracellular events that are caused by the interaction of a gbla subtype-specific agonist such as gabapentin with a heteromer of gb2 and gbla where the heteromer forms a functional GABAβ receptor. An extremely sensitive transcription-based assay is disclosed in Zlokarnik et al., 1998, Science 279:84-88 (Zlokarnik) and also in U.S. Patent No. 5,741,657. The assay disclosed in Zlokarnik and U.S. Patent No. 5,741,657 employs a plasmid encoding β-lactamase under the control of an inducible promoter. This plasmid is transfected into cells together with a plasmid encoding a receptor for which it is desired to identify agonists. The inducible promoter on the β-lactamase is chosen so that it responds to at least one intracellular signal that is generated when an agonist binds to the receptor. Thus, following such binding of agonist to receptor, the level of β-lactamase in the transfected cells increases. This increase in β-lactamase is measured by treating the cells with a cell-permeable dye that is a substrate for cleavage by β-lactamase. The dye contains two fluorescent moieties. In the intact dye, the two fluorescent moieties are physically linked, and thus close enough to one another that fluorescence resonance energy transfer (FRET) can take place between them. Following cleavage of the dye into two parts by β-lactamase, the two fluorescent moieties are located on different parts, and thus can diffuse apart. This increases the distance between the fluorescent moieties, thus decreasing the amount of FRET that can occur between them. It is this decrease in FRET that is measured in the assay. The assay described in Zlokarnik and U.S. Patent No. 5,741,657 can be modified to form an assay for identifying agonists of GABAB receptors by using an inducible promoter to drive β-lactamase where the promoter is activated by an intracellular signal generated by the interaction of agonists and the GABAB receptor. In an alternative version of this assay, cells are treated with a substance that results in the activation of the promoter driving the β-lactamase. This activation is inhibited by a signal generated the interaction of agonists and the GABAB receptor. An example of this alternative version of the assay could employ β-lactamase driven by the CRE promoter where forskolin stimulation of adenylyl cyclase activates the CRE promoter, thus increasing the concentration of β-lactamase in the cells, and this activation of the CRE promoter is inhibited by the interaction of agonists and the GAB Aβ receptor. To produce the GAB Aβ receptor, a plasmid encoding gb2 and a plasmid encoding either gbla, gblb, or gblc are transfected into the cells. The cells are exposed to the cell-permeable dye and then exposed to substances suspected of being agonists of the GABAβ receptor. Those substances that cause a decrease in FRET are likely to actually be agonists of the GABAB receptor. By testing the substances against gbla cells and then against gblb and gblc cells, those substances that are agonists only in gbla cells can be identified. Such substances are gbla subtype-specific agonists. Accordingly, the present invention includes a method for identifying gbla subtype-specific agonists of the GABAB receptor comprising: (a) providing gbla cells comprising: (1) an expression vector that directs the expression of gb2 in the gbla cells; (2) an expression vector that directs the expression of gbla in the gbla cells; (3) an expression vector that directs the expression in the gbla cells of β-lactamase under the control of an inducible promoter that is activated by an intracellular signal generated by the interaction of agonists with the GABAB receptor; (b) exposing the gbla cells to a substrate of β-lactamase that is a cell-permeable dye that contains two fluorescent moieties where the two fluorescent moieties are on different parts of the dye and cleavage of the dye by β-lactamase allows the two fluorescent moieties to diffuse apart; (c) measuring the amount of fluorescence resonance energy transfer (FRET) in the gbla cells in the absence and in the presence of a substance to determine a ratio of the amount of FRET in the absence of the substance to the amount of FRET in the presence of the substance for the gbla cells; (d) providing gblb cells comprising: (4) an expression vector that directs the expression of gb2 in the gblb cells; (5) an expression vector that directs the expression of gblb in the gblb cells; (6) an expression vector that directs the expression in the gblb cells of β-lactamase under the control of an inducible promoter that is activated by an intracellular signal generated by the interaction of agonists with the GABAB receptor; (e) exposing the gblb cells to a substrate of β-lactamase that is a cell-permeable dye that contains two fluorescent moieties where the two fluorescent moieties are on different parts of the dye and cleavage of the dye by β-lactamase allows the two fluorescent moieties to diffuse apart; (f) measuring the amount of FRET in the gblb cells in the absence and in the presence of the substance to determine a ratio of the amount of FRET in the absence of the substance to the amount of FRET in the presence of the substance for the gblb cells; (g) providing gblc cells comprising: (7) an expression vector that directs the expression of gb2 in the gblc cells; (8) an expression vector that directs the expression of gblc in the gblc cells; (9) an expression vector that directs the expression in the gblc cells of β-lactamase under the control of an inducible promoter that is activated by an intracellular signal generated by the interaction of agonists with the GAB Aβ receptor; (h) exposing the gblc cells to a substrate of β-lactamase that is a cell-permeable dye that contains two fluorescent moieties where the two fluorescent moieties are on different parts of the dye and cleavage of the dye by β-lactamase allows the two fluorescent moieties to diffuse apart; (i) measuring the amount of FRET in the gblc cells in the absence and in the presence of the substance to determine a ratio of the amount of FRET in the absence of the substance to the amount of FRET in the presence of the substance for the gblc cells; where if the ratio of the amount of FRET in the absence of the substance to the amount of FRET in the presence of the substance for the gbla cells is greater than the ratio of the amount of FRET in the absence of the substance to the amount of FRET in the presence of the substance for the gblb cells and for the gblc cells then the substance is a gbla subtype-specific agonist. Substeps (l)-(3) of step (a), (4)-(6) of step (d), and (7)-(9) of step (g) can be practiced in any order. The groups of three steps (a)-(c), (d)-(f), and (g)-(i) can be practiced in any order. That is, the method can be practiced, e.g., by first carrying out steps (d)-(f), then (g)-(i), and then (a)-(c). In particular embodiments, the ratio of the amount of FRET in the absence of the substance to the amount of FRET in the presence of the substance for the gbla cells is at least about 50%, preferably about 100%, more preferably about 200%, and even more preferably about 500% greater than the ratio of the amount of FRET in the absence of the substance to the amount of FRET in the presence of the substance for the gblb cells and for the gblc cells. In a particular embodiment of the above-described method, the inducible promoter is a promoter that is activated by changes in membrane currents, e.g., changes in potassium currents. In other embodiments, the inducible promoter is activated by the transcription factor NFAT, or is activated by a signal transduced by a chimeric Gq protein, or a signal generated by protein kinase C activity, or by changes in intracellular calcium levels. In particular embodiments, the inducible promoter is a promoter that is activated by NF-κB or NFAT, e.g., the interleukin 2 promoter (Mattila et al., 1990, EMBO J. 9:4425-4433), a MAPKINASE-inducible promoter, or a promoter that is regulated by cAMP levels, e.g., the CRE promoter (Chen et al., 1995, Anal. Biochem. 226:349-354). When the intracellular signal generated by the interaction of agonists with the GABAβ receptor is an increase in intracellular calcium levels, the cells can also be transfected with a vector encoding a promiscuous G-protein such as G15/16 or Gqi5 or Gqo5. In particular embodiments of the methods described herein, cells are transfected, either stably or transiently, with expression vectors that direct the expression of gb2, gbla, gblb, gblc, β-lactamase under the control of an inducible promoter that is activated by at least one intracellular signal generated by interaction of an agonist with the GABAβ receptor, and/or reporter genes. In other embodiments, the cells are also transfected with a vector encoding a promiscuous G- protein such as G 15/ 16 or Gqi5 or Gqo5. A variety of β-lactamases are known in the art and are suitable for use in the present methods. One particularly well-studied form of β-lactamase is the product of the Ampr gene of E. coli, TEM-1 β-lactamase (Sutcliffe, 1978, Proc. Natl. Acad. Sci. USA 75:3737-3741). A version of TEM-1, with its signal sequence deleted so that it accumulates in the cytoplasm, is disclosed in Kadonaga et al., 1984, J. Biol. Chem. 259:2149-2154. β-lactamases are produced by a variety of bacteria and many β-lactamases have been well studied. For example, Staphlyococcus aureus produces PCI β-lactamase; Bacillus cereus produces a β-lactamase known as β- lactamase I; Escherichia coli produces RTEM β-lactamase (Christensen et al., 1990, Biochem J. 266:853-861. All that is necessary for a particular β-lactamase to be suitable for use in the present invention is that it be capable of cleaving the fluorescent substrate in such a way that the two fluorescent moieties of the substrate can diffuse away from each other following cleavage. This can be easily tested and thus the suitability of a particular β-lactamase can be easily determined. The amino acid sequences of a variety of suitable β-lactamases are disclosed in Ambler, 1980, Phil. Trans. R. Soc. Lond. (Ser. B.) 289:321-331. One of skill in the art can readily synthesize synthetic DNA sequences that encode these β- lactamases. Alternatively, these β-lactamases can be cloned from natural sources. DNA sequences encoding β-lactamases can be placed into suitable expression vectors and transfected into cells for use in the methods of the present invention. A DNA sequence encoding a particular β-lactamase that can be used in the methods of the present invention is shown in SEQ.JJD.NO.:l of U.S. Patent No. 5,741,657 while the corresponding amino acid sequence is shown as SEQ.JD.NO.:2 of U.S. Patent No. 5,741,657. A plasmid containing this DNA (pTG2dell) is described in Kadonaga et al, 1984, J. Biol. Chem. 259:2149-2154. Moore et al., 1997, Anal. Biochem. 247:203-209 describes a method for engineering a form of RTEMl β-lactamase that is maintained intracellularly by eukaryotic cells. DNA encoding the native signal sequence of RTEMl β-lactamase is removed and replaced with a methionine codon. Sequences that provide for optimal translational efficiency in eukaryotes are placed immediately upstream of this methionine by PCR. This modified β-lactamase coding sequence is then cloned into expression vector pRc-CMV (Invitrogen, San Diego, CA). This places the coding sequences under the control of the human intermediate early cytomegalovirus promoter and provides a bovine growth hormone polyadenylation sequence. This construct, known as pCMV-BL, was able to direct the expression of active β- lactamase in the cytoplasm of mammalian cells. A preferred embodiment of the present invention makes use of the fluorescent β-lactamase substrate used in the assays for transcriptional activation described by Zlokarnik et al., 1998, Science 279:84-88. This substrate is known as CCF2/AM and has the following structure where Ac = acetyl; Bt = butyryl; and AM = acetoxymethyl. CCF2/AM contains several ester functionalities. These esters make CCF2/AM membrane-permeant. Because of this membrane-permeant property, CCF2/AM will be taken up by cells growing in tissue culture following addition to the media. After uptake, intracellular esterases cleave the esters, giving rise to CCF2, which is trapped intracellularly due to its many negative charges. The structure of CCF2 is CCF2 contains 7-hydoxycoumarin as the FRET donor at the 7 position, of the cephalosporin moiety. The 7-hydroxycoumarin has a 6-chloro substituent to lower the pKa of CCF2 to 5.1, thus making fluorescence independent of pH at pH values above 6, as well as a glycine spacer betweent the coumarin and the cephalosporin moiety. The fluorescent acceptor is fluorescein, which is attached to the T position of the cephalosporin moiety via a thioether linkage. Excitation of the coumarin donor of intact CCF2 at 409 nm gives rise to FRET emission from the fluorescein acceptor having a peak at 520 nm. After cleavage of CCF2, and the separation of the coumarin and fluorescein, excitation of the coumarin donor gives rise to fluorescent emission from the coumarin having a peak at 447 nm. Of course, excitation need not be done at and emission need not be measured at precisely the wavelengths mentioned above. For example, one could excite at 395 nm and measure emission at 530 nm and 460 nm. In principle, one could measure the amount of FRET by monitoring either (a) a decrease in the emission-of the donor fluorescent reagent following stimulation at the donor's absorption wavelength and/or (b) an increase in the emission of the acceptor reagent following stimulation at the donor's absorption wavelength. In practice, FRET is most effectively measured by emission ratioing. Emission ratioing refers to measuring the ratio of emission by the acceptor and emission by the donor. In one embodiment, it is the ratio of donor emission to acceptor emission that is determined in order to measure the amount of FRET that is occurring. A low ratio indicates an intact CCF2 structure; this means that little β- lactamase is present and therefore a large amount of FRET is occurring. A high ratio indicates that CCF2 has been cleaved by β-lactamase; this means that relatively more enzyme is present and therefore a small amount of FRET is occurring. In another embodiment, it is the ratio of acceptor emission to donor emission that is determined in order to measure the amount of FRET that is occurring. A low ratio indicates that CCF2 has been cleaved by β-lactamase; this means that relatively more enzyme is present and therefore a small amount of FRET is occurring. A high ratio indicates an intact CCF2 structure; this means that little β-lactamase is present and therefore a large amount of FRET is occurring. Emission ratioing can be measured by employing a laser-scanning confocal microscope. Emission ratioing is preferably done by splitting the emitted light from a sample with a dichroic mirror and measuring two wavelength bands (corresponding to the donor and the acceptor emission wavelengths) simultaneously with two detectors. Alternatively, the emitted light can be sampled consecutively at each wavelength (by using appropriate filters) with a single detector. In any case, these and other methods of measuring FRET are well known in the art. The use of emission ratioing in the present methods eliminates many variables that might otherwise confound accurate quantitation such as cell size, cell number, probe concentration, and light intensity. The methods of the present invention are easily monitored with a fluorescence microscope or a plate reader. The present invention can be readily adapted for use in 96 well microtiter plates or even in higher density well plates, allowing for its use in high throughput screening programs. CCF2 is meant to be illustrative of certain preferred substrates for use in the invention. The invention can also be practiced with other fluorescent substrates. A general formula for fluorescent substrates of β-lactamase that are suitable for use in the present invention is: where: one of X and Y is a fluorescent donor moiety or an ester derivative of said fluorescent donor moiety, and the other is a fluorescent acceptor or an ester derivative of said fluorescent acceptor moiety; where fluorescence resonance energy transfer can occur between said fluorescent donor moiety and said fluorescent acceptor moiety; R' is selected from the group consisting of H, lower alkyl and (CH2)nOH, in which n is 0 or an integer from 1 to 5; R" is selected from the group consisting of H, physiologically acceptable metal and ammonium cations, -CHR2θCO(CH2) n CH3, -CHR20C0C(CH3)3, -acylthiomethyl, -acyloxy-alpha-benzyl, -delta-butyrolactonyl, - methoxycarbonyloxymethyl, -phenyl, -methylsulphinylmethyl, -beta- morpholinoethyl, -dialkylaminoethyl, -acyloxyalkyl, -dialkylaminocarbonyloxymethyl and -alkyl, in which R2 is selected from the group consisting of H and lower alkyl and in which n is 0 or an integer from 1 to 5; A is selected from the group consisting of S, O, SO, SO2 and CH2; and Z' and Z" are linkers for the fluorescent donor and acceptor moieties. Preferably, 77 is selected from the group consisting of a direct bond -(CH2)nCONR2(CH2)m-, ~(CH2)nNR2CO(CH 2 )m--, -(CH2) n NR2C0NR2(CH2)m--, --(CH2) n NR3CSNR2(CH2)m--, -(CH2)nCONR3(CH2)pCONR2(CH 2 )m--, ~(CH 2 ) n ~, -(CH 2 )nNR3C0(CH2)pS(CH2)m-, -(CH2)nS(CH 2 )m-, -(CH 2 )nO(CH2) m -, ~(CH2) n NR2(CH 2 )m-, ~(CH 2 ) n SO2NR2(CH2)m--, -(CH 2 )nCO2(CH 2 )m~, in which R is selected from the group consisting of H and lower alkyl; R is selected from the group consisting of hydrogen and lower alkyl; and each of n, m and p is independently selected from the group consisting of 0 and integers from 1 to 4. Preferably, Z" is selected from the group consisting of a direct bond to a heteroatom in Y, -O(CH2) n -, "S(CH2) n --, -NR2(CH 2 )n-, -N+R2 2 (CH2)n-~, -OCONR2(CH2) n ~, ~O 2 C(CH2)n-, -SCSNR2(CH2) n -, --SCSO(CH2) n ~, and in which R2 is selected from the group consisting of H and lower alkyl; and each of n and m is independently selected from the group consisting of 0 and integers from 1 to 4. Suitable fluorescent moieties for the β-lactamase substrates described herein, as well as methods of making the β-lactamase substrates disclosed herein, are disclosed in U.S. Patent No. 5,741,657, the disclosures of which are incorporated by reference herein. The linker in the fluorescent substrate that is cleaved by β-lactamase is preferably a cephalosporin. This is because any molecule (such as a fluorescent moiety) that can be chemically attached to the 3' substituent of a cephalosporin is released upon cleavage of the β-lactam ring of the cephalosporin by β-lactamase (Albrecht et al., 1991, J. Med. Chem. 34:669-675). Thus, a fluorescent moiety attached to the 3' substituent will be released upon cleavage and will diffuse away from another fluorescent moiety that remains attached to the rest of the substrate. In particular embodiments of the above-described methods, the cells express a promiscuous G-protein, e.g., Gαl5 or Gαl6. In other embodiments, the cells have been transfected with an expression vector that directs the expression of a G-protein subunit or subunits. Other transcription-based assays can be used to identify gbla subtype- specific agonists of the GAB Aβ receptor. Such other assays rely on the use of reporter genes (other than β-lactamase) that are under the control of inducible promoters. The inducible promoter is activated by an intracellular signal generated by the interaction of agonists with the GABAB receptor, gbla cells containing the reporter gene are exposed to a suspected agonist and the amount of signal from the reporter gene is measured. If the suspected agonist causes an increase in signal (relative to a suitable control), then the suspected agonist is further tested against gblb cells and gblc cells containing the reporter gene. Those suspected agonists that cause an increase in reporter signal that is at least about three times, preferably about 5 times, and more preferably about 10 times, greater in gbla cells than in either gblb or gblc cells are gbla subtype-specific agonists. Accordingly, the present invention provides a method of identifying gbla subtype-specific agonists comprising: (a) providing gbla cells containing a reporter gene under the control of an inducible promoter that is activated by an intracellular signal generated by the interaction of agonists with the GABAB receptor; (b) exposing the gbla cells to a substance; (c) determining the amount of signal from the reporter gene after exposing the gbla cells to the substance; (d) providing gblb cells containing a reporter gene under the control of an inducible promoter that is activated by an intracellular signal generated by the interaction of agonists with the GABAB receptor; (e) exposing the gblb cells to the substance; (f) determining the amount of signal from the reporter gene after exposing the gblb cells to the substance; (g) providing gblc cells containing a reporter gene under the control of an inducible promoter that is activated by an intracellular signal generated by the interaction of agonists with the GABAB receptor; (h) exposing the gblc cells to the substance; (i) determining the amount of signal from the reporter gene after exposing the gblc cells to the substance; where if the amount of signal in step (c) is at least three times the amount of signal in step (f) and in step (i) then the substance is a gbla subtype- specific agonist. Examples of suitable reporter genes are green fluorescent proteins (GFPs), chloramphenicol acetyl transferase, β-galactosidase, and luciferase. The present invention also includes assays for the identification of gbla subtype-specific agonists where the assays are based upon FRET between a first and a second fluorescent dye where the first dye is bound to one side of the plasma membrane of a cell expressing either a gbla, gblb, or gblc heteromer and the second dye is free to move from one face of the membrane to the other face in response to changes in membrane potential. In certain embodiments, the first dye is impenetrable to the plasma membrane of the cells and is bound predominately to the extracellular surface of the plasma membrane. The second dye is trapped within the plasma membrane but is free to diffuse within the membrane. At normal (i.e., negative) resting potentials of the membrane, the second dye is bound predominately to the inner surface of the extracellular face of the plasma membrane, thus placing the second dye in close proximity to the first dye. This close proximity allows for the generation of a large amount of FRET between the two dyes. Following membrane depolarization, the second dye moves from the extracellular face of the membrane to the intracellular face, thus increasing the distance between the dyes. This increased distance results in a decrease in FRET, with a corresponding increase in fluorescent emission derived from the first dye and a corresponding decrease in the fluorescent emission from the second dye. See figure 1 of Gonzalez & Tsien, 1997, Chemistry & Biology 4:269-277. See also Gonzalez & Tsien, 1995, Biophys. J. 69:1272-1280 and U.S. Patent No. 5,661,035. In certain embodiments, the first dye is a fluorescent lectin or a fluorescent phospholipid that acts as the fluorescent donor. Examples of such a first dye are: a coumarin-labeled phosphatidylethanolamine (e.g., N-(6-chloro-7-hydroxy- 2-oxo-2H~l-benzopyran-3-carboxamidoacetyl)-dimyristoylρhosphatidyl- ethanolamine) or N-(7-nitrobenz-2-oxa-l,3-diazol-4-yl)- dipalmitoylphosphatidylethanolamine); a fluorescently-labeled lectin (e.g., fluorescein-labeled wheat germ agglutinin). In certain embodiments, the second dye is an oxonol that acts as the fluorescent acceptor. Examples of such a second dye are: bis(l,3-dialkyl-2-thiobarbiturate)trimethineoxonols (e.g., bis(l,3-dihexyl-2- thiobarbiturate)trimethineoxonol) or pentamethineoxonol analogues (e.g., bis(l,3- dihexyl-2-thiobarbiturate)pentamethineoxonol; or bis(l ,3-dibutyl-2- thiobarbiturate)pentamethineoxonol). See Gonzalez & Tsien, 1997, Chemistry & Biology 4:269-277 for methods of synthesizing various dyes suitable for use in the present invention. In certain embodiments, the assay may comprise a natural carotenoid, e.g., astaxanthin, in order to reduce photodynamic damage due to singlet oxygen. The present invention includes methods in which the activation of GABAB receptors is coupled to inwardly rectifying potassium channels. Activation of the GAB Aβ receptors results in increased potassium current flow across the plasma membrane of cells expressing potassium channels (e.g., Kir channels). This increased current flow results in a hyperpolarization of the cell membrane that can be detected electrophysiologically via voltage or patch clamp techniques or by use of the membrane potential or channel dyes or FRET-based dyes as described above since such hyperpolarization will result in greater FRET. Accordingly, the present invention provides a method of identifying gbla subtype-specific agonists comprising: (a) providing gbla cells comprising: (1) an expression vector that directs the expression of gb2; (2) an expression vector that directs the expression of gbla; (3) an expression vector that directs the expression of an inwardly rectifying potassium channel; (4) a first fluorescent dye, where the first dye is bound to one side of the plasma membrane; and (5) a second fluorescent dye, where the second fluorescent dye is free to move from one face of the plasma membrane to the other face in response to changes in membrane potential; (b) measuring the amount of fluorescence resonance energy transfer (FRET) in the gbla cells in the presence and in the absence of a substance to determine a ratio of FRET in the absence over FRET in the presence of the substance for the gbla cells; (c) providing gblb cells comprising: (6) an expression vector that directs the expression of gb2; (7) an expression vector that directs the expression of gblb; (8) an expression vector that directs the expression of an inwardly rectifying potassium channel; (9) a first fluorescent dye, where the first dye is bound to one side of the plasma membrane; and (10) a second fluorescent dye, where the second fluorescent dye is free to move from one face of the plasma membrane to the other face in response to changes in membrane potential; (d) measuring the amount of FRET in the gblb cells in the presence and in the absence of the substance to determine a ratio of FRET in the absence over FRET in the presence of the substance for the gblb cells; (e) providing gblc cells comprising: (11) an expression vector that directs the expression of gb2; (12) an expression vector that directs the expression of gblc; (13) an expression vector that directs the expression of an inwardly rectifying potassium channel; (14) a first fluorescent dye, where the first dye is bound to one side of the plasma membrane; and (15) a second fluorescent dye, where the second fluorescent dye is free to move from one face of the plasma membrane to the other face in response to changes in membrane potential; (f) measuring the amount of FRET in the gblc cells in the presence and in the absence of the substance to determine a ratio of FRET in the absence over FRET in the presence of the substance for the gblc cells; where if the ratio of FRET in the absence of the substance over FRET in the presence of the substance for the gbla cells is at least about 50% greater than the ratio of FRET in the absence of the substance over FRET in the presence of the substance for the gblb and the gblc cells then the substance is a gbla subtype- specific agonist. In particular embodiments, the ratio of FRET in the absence of the substance over FRET in the presence of the substance for the gbla cells is at least about 75%, preferably at least about 100%, and even more preferably at least about 200% greater than the ratio of FRET in the absence of the substance over FRET in the presence of the substance for the gblb and the gblc cells. Of course, one of skill in the art would realize that control assays should be run where cells that lack at least one of the items recited in substeps (a) (1)- (2) are exposed to the substance and FRET is measured. The amount of FRET so measured in these control assays should be less than the amount of FRET measured in the presence of the substance in step (b) above. This will ensure that the substance is not acting through a mechanism that has nothing to do with the gbla heteromer. In general, one of skill in the art would understand that control assays may be desirable for the assays described herein, in order to ensure that the effects measured come about through interaction of substances with the gbla heterodimer. Another type of control assay that will generally be desirable is to test gblb cells and gblc cells for the presence of functional GABAB receptors that are gblb or gblc heteromers by determining whether GABA can increase a functional GAB Aβ receptor response in those cells. One of skill in the art would understand how to set up such control assays based on the teachings herein combined with knowledge generally known in the art. Inwardly rectifying potassium channels that are suitable for use in the methods of the present invention are disclosed in, e.g., Misgeld et al., 1995, Prog. Neurobiol. 46:423-462; North, 1989, Br. . Pharmacol. 98: 13-23; Gahwiler et al.,1985, Proc. Natl. Acad. Sci USA 82:1558-1562; Andrade et al, 1986, Science 234:1261-1265. In particular embodiments of the above-described methods, the first fluorescent dye is selected from the group consisting of: a fluorescent lectin; a fluorescent phospholipid; a coumarin-labeled phosphatidylethanolamine; N-(6- chloro-7-hydroxy-2-oxo-2H-l-benzopyran-3-carboxamidoacetyl)- dimyristoylphosphatidyl-ethanolamine); N-(7-nitrobenz-2-oxa-l,3-diazol-4-yl)- dipalmitoylphosphatidylethanolamine); and fluorescein-labeled wheat germ agglutinin. In particular embodiments of the above-described methods, the second fluorescent dye is selected from the group consisting of: an oxonol that acts as the fluorescent acceptor; bis(l,3-dialkyl-2-thiobarbiturate)trimethineoxonols; bis(l,3- dihexyl-2-thiobarbiturate)trimethineoxonol; bis(l,3-dialkyl-2-thiobarbiturate) quatramethineoxonols; bis(l,3-dialkyl-2-thiobarbiturate)pentamethineoxonols; bis(l ,3-dihexyl-2-thiobarbiturate)pentamethineoxonol; bis(l ,3-dibutyI-2- thiobarbiturate)pentamethineoxonol); and bis(l,3-dialkyl-2- thiobarbiturate)hexamethineoxonols . The GABAβ receptor belongs to the class of proteins known as G- protein coupled receptors (GPCRs). GPCRs transmit signals across cell membranes upon the binding of ligand. The ligand-bound GPCR interacts with a heterotrimeric G-protein, causing the Gα subunit of the G-protein to disassociate from the Gβ and Gγ subunits. The Gα subunit can then go on to activate a variety of second messenger systems. In some cases it is the Gβ or Gγ subunit that activates the second messenger systems. Generally, a particular GPCR is only coupled to a particular type of G- protein. Thus, to observe a functional response from the GPCR, it is necessary to ensure that the proper G-protein is present in the system containing the GPCR. It has been found, however, that there are certain G-proteins that are "promiscuous." These promiscuous G-proteins will couple to, and thus transduce a functional signal from, virtually any GPCR. See Offermanns & Simon, 1995, J. Biol. Chem. 270:15175- 15180 (Offermanns). Offermanns described a system in which cells are transfected with expression vectors that result in the expression of one of a large number of GPCRs as well as the expression of one of the promiscuous G-proteins Gαl5 or Gα 16. Upon the addition of an agonist of the GPCR to the transfected cells, the GPCR was activated and was able, via Gαl5 or Gαl6, to activate the β isoform of phospholipase C, leading to an increase in inositol phosphate levels in the cells. In addition to the G-protein described by Offermans, chimeric G-proteins, such as Gqi5, also exhibit promiscuous coupling of GPCRs to the phospholipase C pathway. Therefore, the present invention includes assays that are essentially the same as the assays described herein using promiscuous G-proteins except that chimeric G- proteins are used instead of promiscuous G-proteins. Chimeric G-proteins are described in, e.g., Joshi et al, 1999, Eur. J. Neurosci. 11:383-388. By making use of these promiscuous G-proteins, it is possible to set up functional assays for the identification of gbla subtype-specific agonists, even in the absence of knowledge of the G-protein with which the GABAB receptor is coupled in vivo. One possibility for utilizing promiscuous G-proteins in connection with the GABAβ receptor includes a method of identifying a gbla subtype-specific agonist comprising: (a) providing gbla cells that express gb2, gbla, and a promiscuous G-protein, where gb2 and gbla form a heteromer representing a functional GABAB receptor; (b) measuring the level of inositol phosphates in the gbla cells; (c) exposing a portion of the gbla cells to a substance; (d) measuring the level of inositol phosphates in the gbla cells that have been exposed to the substance; (e) determining the ratio of the level of inositol phosphates measured in step (d) over the level of inositol phosphates measured in step (b); (f) providing gblb cells that express gb2, gblb, and a promiscuous G-protein, where gb2 and gblb form a heteromer representing a functional GABAβ receptor; (g) measuring the level of inositol phosphates in the gblb cells; (h) exposing a portion of the gblb cells to the substance; (i) measuring the level of inositol phosphates in the gblb cells that have been exposed to the substance; (j) determining the ratio of the level of inositol phosphates measured in step (i) over the level of inositol phosphates measured in step (g); (k) providing gblc cells that express gb2, gblc, and a promiscuous G-protein, where gb2 and gblc form a heteromer representing a functional GABAβ receptor; (1) measuring the level of inositol phosphates in the gblc cells; (m) exposing a portion of the gblc cells to the substance; (n) measuring the level of inositol phosphates in the gblc cells that have been exposed to the substance; (o) determining the ratio of the level of inositol phosphates measured in step (n) over the level of inositol phosphates measured in step (1); where if the ratio measured in step (e) is at least 50% greater than the ratio measured in steps (j) and (o) then the substance is a gbla subtype-specific agonist. In particular embodiments, the ratio measured in step (e) is at least 100%, 200%, or 500% greater than the ratio measured in steps (j) and (o). Levels of inositol phosphates can be measured by monitoring calcium mobilization. Intracellular calcium mobilization is typically assayed in whole cells under a microscope using fluorescent dyes or in cell suspensions via luminescence using the aequorin assay. Alternatively, other assays described herein or known in the art for measuring calcium levels may be employed. In methods related to those described above, rather than using changes in inositol phosphate levels as an indication of GAB Aβ receptor function, potassium currents are measured. This is feasible since the GABAB receptor, like other metabotropic receptors, is coupled to potassium channels. Thus, one could measure GABAβ receptor coupling to GIRKl, GIRK2, GIRK3, GIRK4, or to other potassium channels in oocytes. GIRKs, methods of manipulating oocytes, and methods of measuring potassium channel activity in oocytes and HEK 293 cells are described in Goldin, 1992, Meth. Enzymol. 207:266-279; Quick & Lester, 1994, Meth. Neurosci. 19:261-279; Smith et al., 1998, J. Cell Biol. 273:23321-23326; Kubo et al., 1997, Nature 364:802-806; Krapivinsky et al., 1995, Nature 374:135-141; Dascal et al., 1993, Proc. Natl. Acad. Sci. USA 90: 10235-10239; Jones et al., 1998, Nature 396:674-679; White et al, 1998, Nature 396:679-682; Kaupmann et al., 1998, Nature 396:683-687; Kuner et al., 1999, Science 283:74-77; and references cited therein. In a particular embodiment of the above-described method, the promiscuous G-protein is selected from the group consisting of Gαl5, Gαl6, and chimeric G-proteins such as Gqi5. Expression vectors containing Gαl5 or Gαl6 are known in the art. See, e.g., Offermanns & Simon, 1995, J. Biol. Chem. 270:15175- 15180; Buhl et al., 1993, FEBS Lett. 323:132-134; Amatruda et al, 1993, J. Biol. Chem. 268:10139-10144. The present invention employs cells co-expressing gb2 and gbla, gblb, or gblc, resulting in the formation of GABAB receptors that are gbla, gblb, or gblc heteromers. Such cells are generally produced by transfecting cells that do not normally express GABAB receptors with expression vectors encoding gb2 and gbla, gblb, or gblc and then culturing the cells under conditions such that functional GABAβ receptor heteromers of gbla/gb2, gblb/gb2, or gblc/gb2 are formed. In this way, recombinant host cells expressing functional GABAB receptors are produced. In some embodiments, the present invention may also employ cell lines derived from cerebellum or cortex which naturally express GABAB receptors. Also suitable for use in the present invention are primary cells that have been derived from animal brains, e.g., rat CA1 pyramidal neurons. Recombinant host cells for use in the present invention may be prokaryotic or eukaryotic, including but not limited to, bacteria such as E. coli, fungal cells such as yeast, mammalian cells including, but not limited to, cell lines of human, bovine, porcine, monkey and rodent origin, and insect cells including but not limited to Drosophila and silkworm derived cell lines. Cells and cell lines which are suitable for recombinant expression, many of which are commercially available, include but are not limited to, L cells L-M(TK") (ATCC CCL 1.3), L cells L-M (ATCC CCL 1.2), HEK293 (ATCC CRL 1573), Raji (ATCC CCL 86), CV-1 (ATCC CCL 70), COS-1 (ATCC CRL 1650), COS-7 (ATCC CRL 1651), CHO-K1 (ATCC CCL 61), 3T3 (ATCC CCL 92), NIH 3T3 (ATCC CRL 1658), HeLa (ATCC CCL 2), C127I (ATCC CRL 1616), BS-C- 1 (ATCC CCL 26), MRC-5 (ATCC CCL 171), melanotroph cell lines (e.g., tsA58 [Chronwall et al., 2000, Abstract 622.9 from the 30 th Annual Neuroscience Meeting (Nov. 2000), New Orleans, LA]; mIL39 [Hnasko et al., 1997, Endocrinology 138:5589-5596]), Xenopus melanophores, and Xenopus oocytes. In preferred embodiments, the host cells do not naturally express GABAB receptors in order to make it easier to distinguish the effects of the transfected subunits. Cells that are particularly suitable for use in the present invention are Xenopus oocytes co-expressing gb2 and gbla, gblb, or gblc, in which gb2 has formed a functional heteromer with either gbla, gblb, or gblc. The presence of functional heteromers in such cells can be determined by the use of assays that measure coupling of functional GABAB receptors to inwardly rectifying potassium channels (especially the Kir3 family). In the case of Xenopus oocytes, co-expression of gb2 and gbla, gblb, or gblc is often effected by microinjecting RNA encoding gb2 and RNA encoding gbla, gblb, or gblc into the oocytes rather than by transfecting the oocytes with expression vectors encoding gb2 and gbla, gblb, or gblc. Microinjection of RNA into Xenopus oocytes in order to express proteins encoded by the RNA is well known in the art. Also suitable for use in the present invention are cell lines that have been isolated from animals where the cell lines express gbla heteromers but not gblb or gblc heteromers. One possibility is to derive such cell lines from mouse pituitary tumors. Such cell lines can be obtained from trangenic mice that express the SV40 large T antigen under the control of the pro-opiomelanocortin promoter (Low et al, 1993, J. Biol. Chem. 268:24967-24975). The use of this promoter leads to tissue specific expression of the large T antigen in the mouse pituitary and to the development of intermediate lobe pituitary tumors. From such tumors, melanotroph cell lines can be isolated (see, e.g., the mIL39 cell line described in Hnasko et al., 1997, Endocrinology 138:5589-5596). Many of these melanotroph cell lines express gbla receptors but not gblb or gblc receptors. Thus, they are suitable for use in the methods of the present invention. In a variation of this method, the S V40 large T antigen can be a temperature sensitive version known as tsA58 (see, e.g., the mJJL- tsA58 cell line described in Chronwall et al, 2000, Abstract 622.9 from the 30 th Annual Neuroscience Meeting (Nov. 2000), New Orleans, LA). In order to confirm that the melanotroph cell lines described above express gbla receptors but not gblb or gblc receptors, one can use antisera that are specific for gbla, gblb, or gblc. Such antisera can be raised by standard methods utilizing as immunogens peptides that are unique to the gbla, gblb, or gblc amino acid sequences described herein. Alternatively, one can use antisera that recognize more than one GABAB receptor subunit, relying on the difference in molecular weights of the subunits to distinguish the subunits on Western blots. For an example of such a procedure using an antiserum that recognizes gbla and gblb, see Kaupmann et al., 1998, Nature 396:683-687. Western blotting of melanotroph cell lines that are suitable for use in the methods described herein should indicate the presence of a band corresponding to gbla at a molecular weight of about 130 kDa and no corresponding bands representing gblb (about 100 kDa) or gblc (about 125 kDa). Data presented herein (see Example 11) show that gabapentin (EC50 = 2 μM) inhibited up to 70-80% of the total K+-evoked Ca2+ influx via voltage dependent-calcium channels (VD-CCs) in the mouse pituitary intermediate melanotrope clonal mIL-tsA58 cell line. tsA58 mIL cells endogenously express only gbla heteromers and not also gblb heteromers or gblc heteromers. Moreover, activity of the agonist gabapentin in tsA58 cells was dose-dependently and completely blocked with the GABAB receptor antagonist CGP55845, and was nearly identical to the activity of the prototypic GABAB receptor agonist baclofen in both extent and potency. Antisense knockdown of gbla also completely blocked gabapentin activity while gblb antisense and control oligonucleotides had no effect, indicating that gabapentin inhibition of membrane Ca2+ mobilization in these mIL cells was dependent on a functional gbla heteromer receptor. It has been reported recently that gabapentin is a selective agonist for the recombinant and neuronal GABAB gbla-gb2 heteromer subtype coupled to GIRKs, and that it is not a partial agonist and does not block GABA activity at gblb- gb2 and gblc-gb2 heteromers (Ng et al., 2001, Mol. Pharm. 59:144-152). Selective gabapentin activation of GABAB receptors negatively coupled to VD-CCs may account for gabapentin actions in K+ evoked Ca2+-dependent responses and this notion is also consistent with the depressant action of gabapentin on voltage-sensitive calcium currents in some central neurons (Stefani et al., 1998, Neuropharmacology 37:83-91). Indeed, the data presented herein show that gabapentin is an agonist at brain GABAB gbla-gb2 heteromer receptors endogenously expressed in mIL cells and mediates robust dose-dependent inhibition, similar to that of the prototypical GABAB receptor agonist baclofen, of VD-CC function. These effects of gabapentin can be attributed to selective activity at the GABAB receptor since they could be blocked with GABAB receptor antagonists and selective antisense knockdown of the gbla subunit. This agrees with the selective activity reported at the recombinant GABAβ receptors by Ng et al., 2001, Mol. Pharm. 59:144-152. Recombinant GABAB receptor heteromers have been also shown to couple to calcium channels in cultured NG108-15 cells and sympathetic neurons (Easter et al., 2000, J. Physiol. 523P:192P; Filippov et al., 2000, J. Neurosci. 20:2867- 2874), and activation of native receptors in rat pituitary elanotropes and dorsal root sensory neurons leads to inhibition of calcium currents (Hand et al., 2000, Neurosci. Letts. 290:49-52; Morris et al., 1998, J. Neurochem. 71:1329-1332). The results presented herein also indicate that, in hippocampal neurons in situ, gabapentin activates GABAβ receptors negatively coupled to N- and/or P/Q-type VD-CCs. But the data presented herein do not support a predominant action of gabapentin on L- type Ca2+ channels since gabapentin inhibited subthreshold Ca2+ responses but did not prevent Ca2+ action potentials in the present experiments. Gabapentin actions on neuronal GABAβ receptors coupled to VD-CCs is consistent with the previously reported actions of baclofen in hippocampal neurons (Scholz & Miller, 1991, J. Physiol. (Lond.) 444:669-686; Lambert & Wilson, 1996, J. Physiol. (Lond.) 492:115- 127). The studies cited above and the data presented herein underscore that VD-CCs represent a major and physiologically important effector for neuronal GABAB receptors. The present invention includes a method for identifying a gbla subtype-specific agonist that comprises: (a) determining whether a substance activates a GABAB receptor functional response in a melanotroph cell line that express gbla receptors but not gb 1 b receptors or gb 1 c receptors ; (b) determining whether the substance activates a GAB Aβ receptor functional response in gblb cells; (c) determining whether the substance activates a GAB Aβ receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in the melanotroph cell line, but not in the gblb or gblc cells, then the substance is a gbla subtype-specific agonist. In particular embodiments, the melanotroph cell line is selected from the group consisting of mIL39 cells and mJJL-tsA58 cells. In particular embodiments, the functional response is selected from the group consisting of: modulation of the activity of an ion channel; changes in calcium concentration; changes in a signal from a reporter gene whose expression is controlled by a promoter that is induced by interaction of an agonist with the GABAβ receptor; and changes in membrane currents. In particular embodiments, the change in membrane current is caused by the modulation of the activity of an inwardly rectifying potassium current. In other embodiments, the change in membrane current is caused by the modulation of the activity of a voltage dependent-calcium channel. In particular embodiments, the gblb cells and gblc cells are cells that do not naturally express any GABAB receptor subunits and have been transfected with expression vectors encoding gblb or gblc subunits as well as gb2 subunits so as to form functional gblb or gblc receptors. In particular embodiments, that the substance activates the functional response in a melanotroph cell line via GABAβ receptors is confirmed by demonstrating that the functional response is abolished or diminished by treatment of the melanotroph cells with a specific inhibitor of GABAB receptors (e.g., CGP55845). Also suitable for use in the present invention are GTi neuronal cell lines that have been developed from tumors induced in a trangenic mouse by SV40 large T antigen expression (Martinez de la Escalera et al., 1994, Neuroendocrinology 59:420-425; Mellon et al., 1990, Neuron 5:1-10). In these cells, stimulation of GABAA receptors (e.g., by treatment of the cells with GABAA receptor-specific agonists such as muscimol or benzodiazapines) leads to secretion of gonadotrophin releasing hormone (GnRH). See Martinez de la Escalera et al., 1994, Neuroendocrinology 59:420-425. Stimulation of these cells with gbla subtype specific agonists will lead to an inhibition of GnRH release. Also suitable for use in the present invention are cells that express polypeptides that comprise amino acid sequences that are similar to, but not exactly the same, as the amino acid sequences disclosed herein for gb2, gbla, gblb, and gblc. It is generally accepted that single amino acid substitutions do not usually alter the biological activity of a protein (see, e.g., Molecular Biology of the Gene. Watson et al., 1987, Fourth Ed., The Benjamin/Cummings Publishing Co., Inc., page 226; and Cunningham & Wells, 1989, Science 244:1081-1085). Accordingly, suitable cells for the practice of the present invention include cells containing polypeptides where one amino acid substitution has been made in the gb2, gbla, gblb, or gblc amino acid sequences disclosed herein where the polypeptides still retain substantially the same biological activity as native gb2, gbla, gblb, and gblc. The present invention also includes the use of polypeptides where two, three, four, five, six, seven, eight, nine, ten, or more amino acid substitutions have been made in gb2, gbla, gblb, or gblc amino acid sequences disclosed herein where the polypeptides still retain substantially the same biological activity as native gb2, gbla, gblb, or gblc. In particular, the present invention includes embodiments where the above-described substitutions are conservative substitutions. In particular, the present invention includes embodiments where the above-described substitutions do not occur in the ligand-binding domain of gb2, gbla, gblb, or gblc. In particular, the present invention includes embodiments where amino acid changes have been made in positions of gb2, gbla, gblb, or gblc that have not been evolutionarily conserved. For guidance as to which positions of gb2, gbla, or gblb have not been evolutionarily conserved, one of skill in the art can turn to disclosures such as Figure 1A of Kuner et al., 1999, Science 283:74-77; Figure la of Kaupmann et al, 1998, Nature 396:683-687; Figure la of Jones et al., 1998, Nature 396:674-679; or Figure 1 of White et al, 1998, Nature 396:679-682. Such figures compare the amino acid sequence of gb2 with the amino acid sequences of gbla or gblb. Positions in which gb2 does not share the same amino acid as gbla or gblb are positions that have not been evolutionarily conserved. One could readily create similar comparisons between gb2 and gblc in order to determine positions in the amino acid sequence of gblc that have not been evolutionarily conserved. In order to produce the above-described cells co-expressing gb2 and either gbla, gblb, or gblc, expression vectors comprising DNA encoding gb2, gbla, gblb, and gblc can be transfected into the cells. gb2, gbla, gblb, and gblc can be transfected separately, each on its own expression vector, or, alternatively, a single expression vector that encodes both gb2 and one of either gbla, gblb, or gblc can be used. Transfection is meant to include any method known in the art for introducing expression vectors into the cells. For example, transfection includes calcium phosphate or calcium chloride mediated transfection, lipofection, infection with a retroviral construct, and electroporation. Expression of β-lactamase, reporter genes, and/or promiscuous G-proteins can also be effected by transfection of expression vectors comprising DNA encoding these proteins. A variety of expression vectors can be used to express recombinant gb2, gbla, gblb, gblc, β-lactamase, reporter genes, and/or promiscuous G-proteins. Commercially available expression vectors which are suitable include, but are not limited to, pMClneo (Stratagene), pSG5 (Stratagene), pcDNAI and pcDNAIamp, pcDNA3, pcDNA3.1, pCR3.1 (Invitrogen, San Diego, CA), EBO-ρSV2-neo (ATCC 37593), pBPV-l(8-2) (ATCC 37110), pdBPV-MMTneo(342-12) (ATCC 37224), pRSVgpt (ATCC 37199), pRSVneo (ATCC 37198), pCI.neo (Promega), pTRE (Clontech, Palo Alto, CA), pIRESneo (Clontech, Palo Alto, CA), ρCEP4 (Invitrogen, San Diego, CA), pSCll, pSV2-dhfr (ATCC 37146), and the PT7TS oocyte expression vector (or similar expression vectors containing the globin 5' UTR and the globin 3' UTR). The choice of vector will depend upon cell type used, level of expression desired, and the like. For convenience of detection in the methods described herein, the substances may be labeled, e.g., radioactively, enzymatically, fluorescently, etc. In particular embodiments of the methods described herein, the binding affinity (KD) of the gbla subtype-specific agonist for heteromers of gb2 and gbla is determined. In particular embodiments, such binding affinity is between InM and 200 mM; preferably between 5 nM and 1 mM; more preferably between 10 nM and 100 μM; and even more preferably between 10 nM and 100 nM. The conditions under which cells are exposed to substances in the methods described herein are conditions that are typically used in the art for the study of protein-ligand interactions: e.g., physiological pH; salt conditions such as those represented by such commonly used buffers as PBS or in tissue culture media; a temperature of about 4°C to about 55°C; incubation times of from several minutes to several hours. Generally, the cells are grown in suspension or tissue culture and the substances are added directly to the cells, optionally after first washing away the media. For embodiments using oocytes, the oocytes are generally isolated and held in a bath to which the substances are added at the appropriate times. DNA encoding subunits of the GABAβ receptor can be obtained by isolating cDNA encoding the subunits from suitable cDNA libraries. A suitable cDNA library would be, e.g., an adult human cerebellum cDNA library. Such a library can be prepared by methods well-known in the art. Suitable oligonucleotides for use in isolating subtype-specific cDNAs from such a library can be designed based upon the DNA sequences encoding gbla, gblb, gblc, and gb2 disclosed herein, or based upon the DNA sequences encoding these subunits that are disclosed in the scientific literature. In particular embodiments of the above-described methods, gb2 is a polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ.ID.NO.: 10; Positions 9-941 of SEQ.1D.NO.:10; Positions 35-941 of SEQ.ID.NO.: 10; Positions 36-941 of SEQ.ID.NO.: 10; Positions 38-941 of SEQ.ID.NO.: 10; Positions 39-941 of SEQ.ID.NO.:10; Positions 42-941 of SEQ.ID.NO.: 10; Positions 44-941 of SEQ.ID.NO.: 10; Positions 46-941 of SEQ.ID.NO.: 10; Positions 52-941 of SEQ.ID.NO.: 10; Positions 57-941 of SEQ.ID.NO.: 10; the amino acid sequence in GenBank accession no. AF056085; the amino acid sequence in GenBank accession no. AJ012188; the amino acid sequence in GenBank accession no. AF058795; and the amino acid sequence encoded by the DNA sequence deposited in GenBank accession no. ASF074482. In particular embodiments of the above-described methods, gb2 is a chimeric gb2 protein. By chimeric gb2 protein is meant a contiguous polypeptide sequence of gb2 fused in frame to a polypeptide sequence of a non-gb2 protein. For example, the N-terminal domain and seven transmembrane spanning domains of gb2 fused at the C-terminus in frame to a G protein is a chimeric gb2 protein. Another example of a chimeric gb2 protein is a polypeptide comprising the FLAG epitope fused in frame at the amino terminus of amino acids 52-941 of SEQ.ID.NO.: 10. Especially preferred forms of chimeric gb2 proteins are those in which a non-gb2 polypeptide replaces a portion of the N-terminus of gb2. Chimeric gbla, gblb, and gblc proteins may also be used in the present invention. In particular embodiments, the chimeric gbla, gblb, or gblc protein comprises the entire coding region of gbla, gblb, or gblc except for the signal sequence fused in frame to a polypeptide sequence of a non-gbla, gblb, or gblc protein. In particular embodiments, the expression vector encoding gb2 comprises a nucleotide sequence selected from the group consisting of: Positions 293-3,115 of SEQ.ID.NO.:9; Positions 317-3,115 of SEQ.ID.NO. :9; Positions 395-3,115 of SEQ.ID.NO. :9; Positions 398-3,115 of SEQ.JJD.NO.:9; Positions 404-3,115 of SEQ.ID.NO.:9; Positions 407-3,115 of SEQ.ID.NO.:9; Positions 416-3,115 of SEQ.ID.NO. :9; Positions 422-3,115 of SEQ.ID.NO. :9; Positions 428-3,115 of SEQ.JD.NO.:9; Positions 446-3,115 of SEQ.ID.NO.:9; and Positions 461-3,115 of SEQ.ID.NO.:9. In particular embodiments of the above-described methods, gbla is a polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ.ID.NO.:2; SEQ.ID.NO.:4; and the GABAβRla amino acid sequence reported in Kaupmann et al., 1997, Nature 386:239-246;:239-246. In particular embodiments of the methods described herein, gblb is rat gblb and has the amino acid sequence known as GABAβRlb reported in Kaupmann et al., 1997, Nature 386: 239-246 or is human gblb and has the amino acid sequence encoded by the DNA sequence deposited in GenBank accession no. AJ225029 or AJ012186 or is SEQ.ID.NO.:6. The assays described above could be modified to identify gbla subtype-specific inverse agonists. In such assays, gbla subtype-specific inverse agonists would be identified through a change in the signal that is being assayed that is the opposite of the change that is observed with an agonist. For example, in the assays using β-lactamase reporter genes, gbla subtype-specific inverse agonists would lead to a decrease in β-lactamase activity under conditions where gbla subtype-specific agonists lead to an increase. Similarly, gbla subtype-specific inverse agonists can be identified by modifying the functional assays that monitor decreases in cAMP levels. In the case of assays for gbla subtype-specific inverse agonists, increases in cAMP levels would be observed. Some of the methods described herein can be modified in that, rather than exposing whole cells to substances, membranes can be prepared from the cells and those membranes can be exposed to the substances. Such a modification utilizing membranes rather than cells are especially suitable for those methods that involve measuring the binding of the substances to cells. It may occasionally be sufficient to determine that a substance is an agonist that is specific for the gbla heteromer as opposed to the gblb heteromer without also determining the agonist's effect, if any, on the gblc heteromer. In such cases, the methods described herein can be modified so that they are performed essentially the same way as described above for identifying gbla subtype-specific agonists, but the steps that determine the substance's effect on the gblc heteromer are not carried out. Accordingly, the present invention also includes the following methods: A method of identifying substances that are specific for the gbla heteromer as opposed to the gblb heteromer that comprises (a) determining that a substance is an agonist of GABAB receptors comprising a gbla subunit; and (b) determining that the substance is not an agonist of GABAβ receptors comprising a gblb subunit. In particular embodiments, the method furthermore comprises one or more of the following steps: (c) determining that the substance activates post-synaptic potassium currents; (d) determining that the substance does not presynaptically depress GABA inhibitory postsynaptic currents; (e) determining that the substance is not an agonist of GABAA receptors; (f) determining that the substance is an agonist of GABAB receptors that are negatively coupled to voltage dependent-calcium channels. A method of identifying substances that are specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) exposing a substance, separately, to gbla cells and gblb cells; (b) quantitating the binding of the substance to the gbla cells and gblb cells; where, if the amount of binding of the substance to the gbla cells is at least 3 times greater than the amount of binding of the substance to the gblb cells, then the substance is specific for the gbla heteromer as opposed to the gblb heteromer. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer that comprises: (a) providing gbla cells; (b) exposing the gbla cells to gabapentin or pregabalin in the presence and in the absence of a substance; (c) measuring the binding of gabapentin or pregabalin to the gbla heteromers in the presence and in the absence of the substance; where, if the amount of binding of gabapentin or pregabalin in step (c) is less in the presence of the substance than in the absence of the substance, then; (d) determining whether the substance binds to gblb cells; where, if the substance does not bind to gblb cells, then the substance is a substance that is specific for the gbla heteromer as opposed to the gblb heteromer. In particular embodiments; the gbla cells comprise an expression vector encoding gb2 and an expression vector encoding gbla and the gbla cells are cultured under conditions such that gb2 and gbla are expressed and gbla heteromers are formed; and the gblb cells comprise an expression vector encoding gb2 and an expression vector encoding gblb and the gblb cells are cultured under conditions such that gb2 and gblb are expressed and gblb heteromers are formed. In particular embodiments, the method further comprises determining whether the substance that is specific for the gbla heteromer as opposed to the gblb heteromer activates a functional response of a gbla receptor. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) providing a Xenopus laevis oocyte expressing gbla and gb2 so as to form a functional gbla heteromer in the oocyte where the oocyte also expresses a Kir; (b) exposing the oocyte of step (a) to a substance while monitoring potassium ion flow across the oocyte membrane; (c) providing a Xenopus laevis oocyte expressing gblb and gb2 so as to form a functional gblb heteromer in the oocyte where the oocyte also expresses a Kir; (d) exposing the oocyte of step (c) to the substance while monitoring potassium ion flow across the oocyte membrane; where if the exposure of the oocytes to the substance results in increased potassium ion flow in step (b) but not in step (d) then the substance is a substance that is specific for the gbla heteromer as opposed to the gblb heteromer. In particular embodiments; (i) the oocytes of step (a) have been microinjected with RNA encoding gbla, gb2, and a Kir; (ii) the oocytes of step (c) have been microinjected with RNA encoding gblb, gb2, and a Kir. In particular embodiments, the monitoring of steps (b) and (d) is done by patch clamp recordings. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) determining whether a substance activates a GABAB receptor functional response in gbla cells; (b) determining whether the substance activates a GABAB receptor functional response in gblb cells; where if the substance activates a GABAB receptor functional response in gbla cells, but not in gblb, then the substance is specific for the gbla heteromer as opposed to the gblb heteromer. In particular embodiments, the functional response is a decrease in intracellular calcium levels. In particular embodiments, the decrease in intracellular calcium levels is measured by the use of a calcium indicator dye. In particular embodiments, the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) providing gb 1 a cells ; (b) loading the gbla cells with a calcium indicator dye; (c) measuring a fluorescence characteristic of the calcium indicator dye in the gbla cells in the presence and in the absence of a substance; (d) providing gb 1 b cells ; (e) loading the gblb cells with a calcium indicator dye; (f) measuring a fluorescence characteristic of the calcium indicator dye in the gblb cells in the presence and in the absence of the substance; where if a change in fluorescent characteristic in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) then the substance is a substance that is specific for the gbla heteromer as opposed to the gblb heteromer. In particular embodiments, the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. In particular embodiments, the change in fluorescent characteristic is an increase in intensity of a fluorescence emission maximum, a shift in the wavelength of an emission maximum, or a shift in the wavelength of an absorption maximum. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer that comprises: (a) determining whether a substance activates a GABAB receptor functional response in a melanotroph cell line that express gbla receptors but not gblb receptors; (b) determining whether the substance activates a GABAB receptor functional response in gblb cells; where if the substance activates a GABAB receptor functional response in the melanotroph cell line, but not in the gblb, then the substance is specific for the gbla heteromer as opposed to the gblb heteromer. In particular embodiments, the melanotroph cell line is selected from the group consisting of mIL39 cells and mIL-tsA58 cells. In particular embodiments, the functional response is selected from the group consisting of: modulation of the activity of an ion channel; changes in calcium concentration; changes in a signal from a reporter gene whose expression is controlled by a promoter that is induced by interaction of an agonist with the GABAB receptor; and changes in membrane currents. In particular embodiments, the change in membrane current is caused by the modulation of the activity of an inwardly rectifying potassium current or the modulation of the activity of a voltage dependent-calcium channel. In particular embodiments, the gblb cells are cells that do not naturally express any GABAB receptor subunits and have been transfected with expression vectors encoding gblb subunits as well as gb2 subunits so as to form functional gblb receptors. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) providing gbla cells that express apoaequorin; (b) loading the gbla cells with coelenterazine so that aequorin is formed in the gbla cells; (c) measuring the emission of light caused by the interaction of calcium and the aequorin in the gbla cells in the presence and in the absence of a substance; (d) providing gblb cells that express apoaequorin; (e) loading the gblb cells with coelenterazine so that aequorin is formed in the gblb cells; (f) measuring the emission of light caused by the interaction of calcium and the aequorin in the gblb cells in the presence and in the absence of the substance; where if less light emission in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) then the substance is specific for the gbla heteromer as opposed to the gblb heteromer. It may occasionally be sufficient to determine that a substance is an agonist that is specific for the gbl heteromer as opposed to the gblc heteromer without also determining the agonist's effect, if any, on the gblb heteromer. In such cases, the methods described herein can be modified so that they are performed essentially the same way as described above for identifying gbla subtype-specific agonists, but the steps that determine the substance's effect on the gblb heteromer are not carried out. Accordingly, the present invention also includes the following methods: A method of identifying substances that are specific for the gbla heteromer as opposed to the gblc heteromer that comprises (a) determining that a substance is an agonist of GABAB receptors comprising a gbla subunit; and (b) determining that the substance is not an agonist of GAB Aβ receptors comprising a gblc subunit. In particular embodiments, the method furthermore comprises one or more of the following steps: (c) determining that the substance activates post-synaptic potassium currents; (d) determining that the substance does not presynaptically depress GABA inhibitory postsynaptic currents; (e) determining that the substance is not an agonist of GABAA receptors; (f) determining that the substance is an agonist of GABAB receptors that are negatively coupled to voltage dependent-calcium channels. A method of identifying substances that are specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) exposing a substance, separately, to gbla cells and gblc cells; (b) quantitating the binding of the substance to the gbla cells and gblc cells; where, if the amount of binding of the substance to the gbla cells is at least 3 times greater than the amount of binding of the substance to the gblc cells, then the substance is specific for the gbla heteromer as opposed to the gblc heteromer. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer that comprises: (a) providing gbla cells; (b) exposing the gbla cells to gabapentin or pregabalin in the presence and in the absence of a substance; (c) measuring the binding of gabapentin or pregabalin to the gbla heteromers in the presence and in the absence of the substance; where, if the amount of binding of gabapentin or pregabalin in step (c) is less in the presence of the substance than in the absence of the substance, then; (d) determining whether the substance binds to gblc cells; where, if the substance does not bind to gblc cells, then the substance is a substance that is specific for the gbla heteromer as opposed to the gblc heteromer. In particular embodiments; the gbla cells comprise an expression vector encoding gb2 and an expression vector encoding gbla and the gbla cells are cultured under conditions such that gb2 and gbla are expressed and gbla heteromers are formed; and the gblc cells comprise an expression vector encoding gb2 and an expression vector encoding gblc and the gblc cells are cultured under conditions such that gb2 and gblc are expressed and gblc heteromers are formed. In particular embodiments, the method further comprises determining whether the substance that is specific for the gbla heteromer as opposed to the gblc heteromer activates a functional response of a gbla receptor. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) providing a Xenopus laevis oocyte expressing gbla and gb2 so as to form a functional gbla heteromer in the oocyte where the oocyte also expresses a Kir; (b) exposing the oocyte of step (a) to a substance while monitoring potassium ion flow across the oocyte membrane; (c) providing a Xenopus laevis oocyte expressing gblc and gb2 so as to form a functional gblc heteromer in the oocyte where the oocyte also expresses a Kir; (d) exposing the oocyte of step (c) to the substance while monitoring potassium ion flow across the oocyte membrane; where if the exposure of the oocytes to the substance results in increased potassium ion flow in step (b) but not in step (d) then the substance is a substance that is specific for the gbla heteromer as opposed to the gblc heteromer. In particular embodiments; (i) the oocytes of step (a) have been microinjected with RNA encoding gbla, gb2, and a Kir; (ii) the oocytes of step (c) have been microinjected with RNA encoding gblc, gb2, and a Kir. In particular embodiments, the monitoring of steps (b) and (d) is done by patch clamp recordings. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) determining whether a substance activates a GABAB receptor functional response in gbla cells; (b) determining whether the substance activates a GABAB receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in gbla cells, but not in gblc, then the substance is specific for the gbla heteromer as opposed to the gblc heteromer. In particular embodiments, the functional response is a decrease in intracellular calcium levels. In particular embodiments, the decrease in intracellular calcium levels is measured by the use of a calcium indicator dye. In particular embodiments, the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) providing gbla cells; (b) loading the gbla cells with a calcium indicator dye; (c) measuring a fluorescence characteristic of the calcium indicator dye in the gbla cells in the presence and in the absence of a substance; (d) providing gblc cells; (e) loading the gblc cells with a calcium indicator dye; (f) measuring a fluorescence characteristic of the calcium indicator dye in the gblc cells in the presence and in the absence of the substance; where if a change in fluorescent characteristic in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) then the substance is a substance that is specific for the gbla heteromer as opposed to the gblc heteromer. In particular embodiments, the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. In particular embodiments, the change in fluorescent characteristic is an increase in intensity of a fluorescence emission maximum, a shift in the wavelength of an emission maximum, or a shift in the wavelength of an absorption maximum. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer that comprises: (a) determining whether a substance activates a GABAβ receptor functional response in a melanotroph cell line that express gbla receptors but not gblc receptors; (b) determining whether the substance activates a GABAB receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in the melanotroph cell line, but not in the gblc cells, then the substance is specific for the gbla heteromer as opposed to the gblc heteromer. In particular embodiments, the melanotroph cell line is selected from the group consisting of mIL39 cells and mIL-tsA58 cells. In particular embodiments, the functional response is selected from the group consisting of: modulation of the activity of an ion channel; changes in calcium concentration; changes in a signal from a reporter gene whose expression is controlled by a promoter that is induced by interaction of an agonist with the GABAB receptor; and changes in membrane currents. In particular embodiments, the change in membrane current is caused by the modulation of the activity of an inwardly rectifying potassium current or the modulation of the activity of a voltage dependent-calcium channel. In particular embodiments, the gblc cells are cells that do not naturally express any GABAβ receptor subunits and have been transfected with expression vectors encoding gblc subunits as well as gb2 subunits so as to form functional gblc receptors. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) providing gbla cells that express apoaequorin; (b) loading the gbla cells with coelenterazine so that aequorin is formed in the gbla cells; (c) measuring the emission of light caused by the interaction of calcium and the aequorin in the gbla cells in the presence and in the absence of a substance; (d) providing gblc cells that express apoaequorin; (e) loading the gblc cells with coelenterazine so that aequorin is formed in the gblc cells; (f) measuring the emission of light caused by the interaction of calcium and the aequorin in the gblc cells in the presence and in the absence of the substance; where if less light emission in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) then the substance is specific for the gbla heteromer as opposed to the gblc heteromer. It may occasionally be desirable to identify substances that are gblb subtype-specific or gblc subtype-specific agonists of the GABAβ receptor. In such instances, it will be evident to one skilled in the art that the assays described herein can be modified to identify such gblb subtype-specific or gblc subtype-specific agonists. In general, this can be done by running the same assays but looking for agonist activity (e.g., activation of a functional response) when the substances are added to gblb cells or gblc cells but not when the substances are added to gbla cells. For example, if one were interested in identifying a gblb subtype- specific agonist, one could run an assay such as the following: (a) determining whether a substance activates a GABAB receptor functional response in gbla cells; (b) determining whether the substance activates a GAB Aβ receptor functional response in gblb cells; (c) determining whether the substance activates a GABAB receptor functional response in gb 1 c cells ; where if the substance activates a GAB Aβ receptor functional response in the gblb cells, but not in the gbla or gblc cells, then the substance is a gblb subtype-specific agonist. Similarly, if one were interested in identifying a gblc subtype-specific agonist, one could run an assay such as the following: (a) determining whether a substance activates a GABAβ receptor functional response in gbla cells; (b) determining whether the substance activates a GABAB receptor functional response in gblb cells; (c) determining whether the substance activates a GABAB receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in the gblc cells, but not in the gbla or gblb cells, then the substance is a gblc subtype-specific agonist. Some of the methods described herein can be modified to take advantage of other ways of assaying for agonist activity at the GAB Aβ receptor. Agonists and inverse agonists may affect the internalization or trafficking of functional GAB Aβ receptors. For example, in the case of the β2-adrenergic receptor, agonist exposure results in receptor internalization. It may be that GABAβ receptor trafficking is modulated by agonists in a similar manner. Therefore, the measurement of receptor trafficking between intracellular pools and the cytoplasmic membrane may be considered an assay of agonist activity. It would then be possible to identify agonist activity by monitoring GABAB receptor trafficking. Such trafficking can be monitored by whole cell immunohistochemistry and confocal microscopy or by surface and intracellular receptor labeling and flow cytometry. Furthermore, because the functional GAB Aβ receptor may be a heterodimer, then agonists and inverse agonists may be expected to alter the ratio of heterodimer to monomer. Hence the disruption or appearance of a heterodimer may be considered an additional screening assay. In this case, the monitoring of receptor dimerization or disappearance may be done by the appearance or disruption of FRET. Each of the monomers are labeled with a fluorophore such that close proximity would allow FRET to occur. Upon agonist binding, one might see disruption of FRET, indicating disruption of dimers or increase in FRET indicating more dimerization in the course of agonist activation. Another possibility is to use a microphysiometer to monitor agonist activity. The activation of many receptor pathways is associated with changes in extracellular or intracellular pH. Thus, GABAβ receptor agonists can likely be identified by the use of a microphysiometer to detect such changes when cells expressing GABAB receptors are exposed to suspected agonists. The use of microphysiometers is described in Ng et al., 1999, J. Cell. Biochem. 72:517-527 and Fischer et al., 1999, J. Membr. Biol. 168:39-45. While the above-described methods are explicitly directed to testing whether "a" substance is a gbla subtype-specific agonist of the GABAβ receptor, it will be clear to one skilled in the art that such methods are generally used to test collections of substances, e.g., combinatorial libraries, collections of natural produces, the products of a medicinal chemistry lead optimization program, etc., to determine whether any members of such collections are gbla subtype-specific agonists. Accordingly, the use of collections of substances, or individual members of such collections, as the substance in the above-described methods is within the scope of the present invention. The methods of the present invention are generally described as making use of "a" first cell and "a" second cell, or "a" gbla cell, "a" gblb cell, or "a" gblc cell. The use of the singular article is for the sake of clarity of explanation. Those skilled in the art will understand that the methods will usually be practiced with a plurality, often thousands or even millions, of cells, as when cells are grown in tissue culture and then used in the methods. "Substances" can be any substances that are generally screened in the pharmaceutical industry during the drug development process. For example, substances may be low molecular weight organic compounds (e.g., having a molecular weight of less than about 1,000 daltons); RNA, DNA, antibodies, peptides, or proteins. In particular embodiments of the herein-described methods, the substance is a compound that is produced by modifying the structure of gabapentin by methods of medicinal chemistry. As is well known in the art, it is common to modify a "lead" compound having a particular pharmacological activity (e.g., gabapentin) by sequentially replacing the functional groups of the compound (e.g., amine groups, methyl groups, carboxyl groups, phenolic groups, azido groups, etc.) with different functional groups and testing the modified compounds to determine what effect such replacement has on the compound's pharmacological properties. In such a manner, compounds having improved pharmacological properties such as higher target specificity, more potent agonist or antagonist activity, or lower toxicity can be developed. Comparison of the structures of such modified compounds with the pharmacological properties of the modified compounds can be especially informative in suggesting portions of the compounds which should be conserved and portions which should be varied in order to arrive at a compound with optimal properties. Methods of medicinal chemistry such as these can be applied to gabapentin and the modified gabapentin-like compounds so produced can be tested in the various methods described herein to determine if they possess desirable properties such as, e.g., the property of being a gbla subtype-specific agonist. In particular embodiments of the herein-described methods, the substance is a 3-alkyl substituted GABA analog. gbla subtype-specific agonists identified by the above-described methods are useful in the same manner as other gbla subtype-specific agonists, e.g., gabapentin. Gabapentin has been sold since 1994 in the United States as a treatment for epilepsy under the name NEURONTIN® and, in clinical trials, has been shown to be useful in the treatment of diabetic neuropathy and post-herpetic neuralgia. Given the wide range of utility displayed by gabapentin, it is clear that those skilled in the art would consider the gbla subtype-specific agonists identified by the methods of the present invention to be pharamacologically useful. In particular, it is expected that the gbla subtype-specific agonists identified by the methods of the present invention will be useful in the treatment of such conditions as psychiatric disorders, e.g., bipolar disorders, social phobias, and anxiety; epilepsy and other convulsant disorders; incontinence; gastroesophogeal reflux; cocaine addiction; neurodegenerative disorders such as amyotrohic lateral sclerosis; and multiple chronic pain states such as diabetic neuropathy or post- herpetic neuralgia. Methods of making gabapentin and gabapentin-like compounds are described in U.S. Patent No. 4,024,175 and U.S. Patent No. 4,152,326. The following non-limiting examples are presented to better illustrate the invention. EXAMPLE 1 Receptor expression constructs The human gbla, gblb and gblc isoforms were obtained from human cerebellum cDNA (Clontech, Palo Alto, CA) by PCR cloning using Advantage-HF® PCR kit (Clontech, Palo Alto, CA) and primers based on gbla (Genbank accession no. AJ225028) and gblb (Genbank accession no. A225029) mRNA sequences deposited in Genbank. The cloning of the human gb2 receptor DNA (Genbank accession no.AF069755) has been reported elsewhere (Ng et al., 1999, Genomics 56:288-295). A gb2 construct encoding a modified influenza hemagglutinin signal sequence (MKTIIALSYJJFCLVFA; SEQ,JX>.NO.:ll) followed by an antigenic FLAG (DYKDDDDK; SEQ,ID.NO.:12) epitope, herein referred to as FLAG-gb2, or a gb2 construct encoding the bovine GABAA α l signal sequence (MKKSPGLSDYLWAWTLFLSTLTGRSYGQPSLQD; SEQ.ID.NO.: 13) followed by a c-myc epitope (EQKLISEEDLN; SEQ,ID.NO.:14), herein referred to as cmyc- gb2, were used for transient expression in Xenopus oocytes. All GABAB receptor DNAs were subcloned into the pT7TS Xenopus oocyte expression vector (a gift from Dr. Paul Krieg). It is believed that the use of other Xenopus oocyte expression vectors would produce similar results. M2 muscarinic receptor and Gsα cDNAs were generously supplied by BioSignal (Montreal, Canada). EXAMPLE 2 Materials Gabapentin was extracted from NEURONTIN® capsules (10 capsules, containing 400 mg of gabapentin) in boiling ethanol. After filtration through celite, the solid was triturated in isopropanol (30 ml) to give 3.21 g of a solid containing 85% gabapentin and 15% dextrose. Pure gabapentin was obtained by extraction of the celite cake in boiling methanol, filtration of the light suspension at room temperature and trituration of the residue in ether to yield 1.00 g of a white solid. The white solid was further purified using preparative HPLC with on-line mass spectrometric detection. The collected peak was evaporated to dryness and reconstituted for NMR analysis. The mass spectral and NMR data were consistent with gabapentin. Gabapentin was also obtained commercially from Sigma (St. Louis, MO). Gabapentin was stored at -20°C, and freshly prepared and used immediately in the functional assays. GABA, the active enantiomer (R)-baclofen, and CGP55845 were purchased from Sigma and Tocris Cookson, respectively. CGP71872 was synthesized as previously reported (Belley et al., 1999, Bioorganic Med. Chem. 7:2697-2704). Indo-1 AM, indo-1 pentapotassium salt, carboxy SNARF-1 AM, carboxy SNARF-1, pluronic F-127, and Ca2+ calibration kits were purchased from Molecular Probes, Inc (Eugene, OR). PTX, Pen/Strep and dimethylsulfoxide were obtained from Sigma Chemical (St. Louis, MO). The DME and the Gibco BRL trypsin-free buffer were purchased from Life Technologies (Grand Island, NY). Other chemicals and reagents were purchased from Fisher Scientific (St. Louis, MO). EXAMPLE 3 Xenopus oocyte expression Xenopus oocytes were isolated and recordings performed as described (Ng et al., 1999, J. Biol. Chem. 274:7607-7611; Hebert et al., 1994, Proc. Royal Soc. London, Series B 256:253-261) with the following modifications. After a brief (10 min.) hypertonic shock with 125 mM potassium phosphate pH 6.5, oocytes were allowed to recover in Barth's solution for 1-2 hr. cDNA constructs for various Kir (Kir 3.1 or Kir 3.2) channel isoforms, human gbla, gblb and gblc, human c-myc, gb2, murine gbla and flag-gb2 constructs, human M2 muscarinic receptor, human α2-adrenergic receptor and bovine Gsα were linearized by restriction enzymes and purified using Geneclean (Bio 101). Capped mRNA was made using T7 RNA polymerase and the mMessage mMachine (Ambion). mRNA synthesis for channel and receptor constructs was confirmed by loading aliquots of synthesis reactions on denaturing formaldehyde agarose gels. Individual oocytes were injected with 5-10 ng of RNA (in 25-50 nL) encoding the various murine or human GAB Aβ receptor subunits and human Kir 3.1/3.2 or with the α2AR/Gsα or M2 muscarinic receptor co- expressed with Kir 3.2. Currents were recorded after 48 hr. Standard recording solution was KD-98, 98 mM KC1, 1 mM MgCl2, 5 mM K-HEPES, pH 7.5 unless otherwise stated. Microelectrodes were filled with 3 M KC1 and had resistances of 1- 3 MΩ and 0.1-0.5 MΩ for voltage and current electrodes, respectively. In addition, current electrodes were backfilled with 1% agarose (in 3M KC1) to prevent leakage as described in Hebert et al., 1994, Proc. Royal Soc. London, Series B 256:253-261. Recordings were made at room temperature using a Geneclamp 500 amplifier (Axon Instruments). Oocytes were voltage clamped and perfused continuously with different recording solutions. Currents were evoked by 500 msec voltage commands from a holding potential of -10 mV, delivered in 20 mV increments from -140 to 60 mV to test for inward rectifying potassium currents. Data were recorded at a holding potential of -80 mV and drugs were added to the bath with a fast perfusion system. Data collection and analysis were performed using pCLAMP v6.0 (Axon Instruments) and Origin v4.0 (MicroCal) software. For subtraction of endogenous and leak currents, records were obtained in ND-96, 96 mM NaCl, 2 mM KC1, 1 mM MgCl2, 5 mM Na-HEPES and these were subtracted from recordings in KD-98 before further analysis. EXAMPLE 4 Hippocampal slices and whole cell recordings Transverse hippocampal slices were obtained from male Sprague- Dawley rats (29-40 days postnatal) as described previously (Ouardouz & Lacaille, 1997, J. Neurophysiol. 77:1939-1949: Chapman & Lacaille, 1999, J. Neurosci. 19:8637-8645). Animals were anesthetized with halothane prior to decapitation. The brain was removed from the skull and submerged in cold ACSF (124 mM NaCl, 2.5 mM KC1, 1.25 mM NaH2PO4, 2 mM MgSO4, 2 mM CaCl2, 26 mM NaHCO3 and 10 mM dextrose saturated with 95% 02 and 5% CO2. Hippocampal slices (300 μm) were cut with a vibratome as described previously (Ouardouz & Lacaille, 1997, J. Neurophysiol. 77: 1939-1949) and transferred to a holding chamber for at least 1 hour prior to recording. For whole cell recordings, individual slice were submerged in a chamber mounted on an upright microscope (Zeiss Axioskop) and perfused with ACSF at a flow rate of 2.5 to 3.0 ml/min. All solutions were applied at room temperature. CA1 pyramidal neurons were visualized using DIC and an infrared CCD camera (Cohu 6500). Patch pipettes (4 to 8 MΩ) were filled with (in mM): 140 K-gluconate, 5 NaCl, 2 MgCl2, 10 HEPES, 0.5 EGTA, 2 ATP-Tris, 0.4 GTP-Tris, 1 phosphocreatine, 0.1% biocytin, pH adjusted to 7.2 to 7.3 with KOH. Whole cell voltage clamp recordings were made with an Axopatch 200 amplifier (Axon instruments) with low-pass filtering at 10 kHz. Currents were digitized and stored for future analysis (pClamp, Axon Instruments). Voltage measurements were corrected for liquid junction potentials (Neher, 1992, Meth. Enzymol. 207:123-131). All drugs were bath applied. Baclofen and gabapentin currents were obtained as described previously (Nurse & Lacaille, 1999, Neuropharmacol. 38:1733-1742), using membrane potential ramps and a subtraction procedure. Monosynaptic fast GABA IPSCs were evoked by placing an ultra-small concentric bipolar electrode (Frederick Haer 16-75-3) in stratum radiatum within close proximity to the pyramidal neuron and applying constant current pulses (0-200 μA, 0.05 ms). Glutamatergic non- NMDA and NMDA EPSCs were blocked by perfusing the slices with ACSF containing 20 μM CNQX (RBI) and 50 μM AP5 (RBI), respectively. (-)Baclofen (RBI), gabapentin (Sigma), and the GABAB antagonist CGP55845 (Tocris) were bath applied. The GABAβ agonist (-)baclofen was bath applied at Vhold = -60 mV. I-V relations were obtained during membrane potential ramps from -60 to -160 mV over a 800 ms period, first in control ACSF and then in the presence of drug. Averaged currents were obtained from 3 successive responses in each condition. Agonist currents were isolated by subtracting currents in control ACSF from currents in the presence of the agonist (Iagonist = Il-V,agonist - Ij-V,acsf)- Chord conductance measures were obtained at V m = -80 mV for agonist currents using the formula G m = I / ( - E r ev) where E re v was the observed mean reversal potential for the agonist. The theoretical EK was calculated using the formula EK = RT/F * In [K] 0 /[K]i . Monosynaptic fast GABAA IPSCS were evoked with ultra-small concentric bipolar electrodes (Frederick Haer) placed in stratum radiatum within close proximity to the pyramidal neuron and using constant current pulses (15-90 μA, 0.5 ms) during blockade of non-NMDA and NMDA synaptic transmission with 20 μM CNQX (RBI) and 50μM AP5 (RBI), respectively. Differences between two groups were compared using Student's t-tests (significance level set at α = 0.05). Data are reported as mean ± standard deviation, unless otherwise noted. Histological procedures for revealing biocytin-filled cells were as described previously (Chapman & Lacaille, 1999, J. Neurosci. 19:8637-8645). Briefly, slices were fixed in 4% paraformaldehyde in 0.1 M phosphate buffer, rinsed, and stored at 4°C. Sections were treated with 1% H2O2, washed in 2.5% dimethylsulfoxide and 0.1% Triton X in 0.1 M phosphate buffer, and incubated in avidin-biotin complex (ABC kit, Vectors lab, Burlingame CA). After rinsing, sections were incubated in 0.05% 3'3-diaminobenzidine 4 HCl, 0.02% NiSθ4, 0.1 M imidazole, and 0.001% H2O2 in Tris-buffered saline. Sections were then rinsed and cleared in xylene. Axonal and dendritic arborizations of well-filled cells were examined with a light microscope equipped with a CCD camera. Data are reported as mean ± sem unless otherwise noted. EXAMPLE 5 mIL-tsA58 cells and culture conditions mTL-tsA58 cells were isolated from a mouse intermediate lobe tumor. Briefly, a strain of transgenic mice was generated that developed pituitary tumors because of the melanotrope-specific expression of a pro-opiomelanocortin promoter- Simian Virus 40 Large T antigen (temperature sensitive A58 mutant) fusion gene. The phenotype of these mice was similar to those described previously (Low et al, 1993, J. Biol. Chem. 268: 24967-24975) despite the substitution of the tsA58 mutant T antigen for wildtype. The mIL-tsA58 cells were isolated from a single tumor using procedures analogous to those reported for another melanotrope cell line (Hnasko, 1997, Endocrinology 138: 5589-5596). They express the POMC gene and dopamine D2 receptors. Growth rate and morphology of the cells were similar at 33°C, the permissive temperature for tsA58, and at 37°C. These cells display a normal mouse karyotype after more than 60 passages. They grow either as free floating spheres of tightly associated cells or can be coaxed to adhere to plastic, although they remain clustered under this condition as well. Few individual cells are found in cultures, and the clusters are difficult to dissociate enzymatically without destroying the cells. The mIL cells were maintained in DMEM supplemented with 10% horse serum, 2.5% fetal bovine serum, 100 U/ml PenStrep (10,000 units penicillin and 10 mg streptomycin per ml) 2 mM glutamine and 0.1 mM non-glutamine essential amino acids under 5% CO2 at 37°C. EXAMPLE 6 Measurement of FCa2+]j Kinetics Intracellular calcium ([Ca2+] j) and pH (pH ) were measured simultaneously using a custom-built ultra low light multi-imaging video microscope as described previously (Beatty et al., 1993, Endocrinology 133:972-984; Morris et al., 1994, In: Nuccitelli R (ed.) A Practical Guide to the Study of Ca2+ in Living Cells. Meth. Cell. Biol. 40:183-220). Cells grown on #00 coverslips (Corning, Corning, NY) were simultaneously loaded with 5 μM indo-1/AM and 5 μM SNARF- 1/AM (cell permeant acetoxymethyl (AM) esters), in DMEM, 12.5% dimethylsulfoxide, and 0.04% (w/w) Pluronic F-127 for 30 min at 37°C in a humidified incubator under 10% CO2. After incubation the cells were washed and left in complete medium at 37°C under 10% CO 2 for a 30 min recovery period to allow the esterase to cleave the dyes to their active, impermeant forms. Cells were examined within 90 min following the recovery period. Coverslips with dye-loaded cells were placed in 1.0 ml standard balanced salt solution (138 mM NaCl, 2 mM KC1, 2 mM MgCl2- 10 mM HEPES, 5.5 mM glucose, 2 mM CaCl2, and 50 μM EGTA, pH 7.4) in a microscope stage perfusion chamber maintained at 37°C. Phase contrast and fluorescence images of the cells were obtained simultaneously at 405 nm, 475 nm, 575 nm and 640 nm. Using these images as a guide, up to eight regions of interest (ROIs), each representing a single cell, were defined for Ca2+ (405 and 475 nm images), along with eight corresponding regions for pH (575 and 640 nm images). After 30- to 60- sec of video recording of the [Ca2+]{ and pHi baseline activity, 1.0 ml of an iso- osmotic, high K+ depolarizing solution (10 mM NaCl, 130 mM KC1, 2 mM MgCl2, 10 mM HEPES, 5.5 mM glucose and 2 mM CaCl2, pH 7.4) was added for a final extracellular [K+] of 66 mM. During recordings, the addition of other chemicals or drugs was made directly to the bath in 100-fold excess to achieve the final concentrations indicated. In all cases, osmolarity changed less than 1% by the addition of these agents. Ionomycin (1 μM), a Ca2+ ionophore, was added at the end of some experiments to ensure viability of the cells as well as the responsiveness of the fluorescent dyes. In certain cases, baclofen, gabapentin or the GABAβ receptor agonist CGP55845 was added 5 min prior to, or pertussis toxin 10-14 hours prior to, the exposure of the cells to K+ and the measurement of [Ca2+]j and pHj. The effects of GAB Aβ receptor agonists and antagonists were tested as follows: Five minutes before the start of the baseline recording, drugs were added to the bath to the final concentrations indicated. If both a GAB Aβ receptor agonist and an antagonist were being tested, then the antagonist was added first. After baseline recording, the cells were depolarized with high K+ as described above. EXAMPLE 7 Antisense oligodeoxynucleotide synthesis and administration Two antisense deoxynucleotides (ADN) directed against either GABAβRla (gbla) or GABABRlb (gblb) isoforms of the receptor were designed and synthesized. The gbla ADN is antisense to bases 5'-CAC CAG CAG CAG CAG CAG -3' (a portion of SEQ.ID.NO.: 11) of GABAβRla (bases 4-22, accession number AJ102185) and the gblb ADN is antisense to bases 5' ACA GGG TCC CCC CGG GCC-3' (a portion of SEQ.ID.NO.: 12) of GABAβRlb (bases 4-22, accession number AJ02186). Using the NIH BLAST search engine, these antisense sequences showed extensive overlaps with GABAβRla and GABAβRlb receptor sequences from other species, but had no significant overlaps with sequences of other cDNAs as of December, 2000. A mis-sense probe containing the same nucleotide base content as the gbla ADN, but with bases randomly assigned, was used as a control. This mis- sense probe, 5' CCA GCA GAC ACG CAG CAG -3' (SEQ.ID.NO.: 13) has 8 overlaps with the gbla antisense probe and no known complementarity with other sequences. All nucleotide sequences were synthesized by Integrated DNA Technologies (Coral ville, IA) as phosphorothioated derivatives. For ADN experiments, the mJL cells were exposed to nucleotide for a total of four days, and then tested for Ca2+ channel activity by fluorescence video microscopy. The cells were first cultured in T25 flasks for 1-2 days. The cultures were then placed in 5 ml of serum-free medium and treated with 5 μl of 1.0 mM of the test ADN or mis-sense oligodeoxynucleotide solution (10 μM final concentration). Following a 2 hr incubation at 37°C under 5% CO2, 500 μl of fetal horse serum and 125 μl of fetal bovine serum were added to each flask. Five μl of nucleotide solution were added to each flask at 2 and 3 days of culture. Cells were harvested on day 3 in serum-free medium, and then plated onto cover slips in 12 well plates. The cells were serum-deprived for 30 min at 37°C under 5% CO2 to facilitate adherence to the cover slip, then nucleotide was added to 10 μM final concentration. Serum was added after an additional 30 min and Ca2+ channel activity tested 24 hr later. EXAMPLE 8 Data analysis of [Ca2+1i and pHj measurements Results were analyzed either in real time or from video tape recordings. Twenty-five consecutive frames were averaged in real time, then Ca2+ and pH ratio images of the microscope field (uncorrected for background or shading error) displayed on the RGB display at one image per second. At the same time the integrated gray levels of up to eight regions of interest (ROIs) were extracted from the 25-frame average image and the data stored on an ASKII file for further analysis. In addition, the uncorrected ratio values for Ca2+ and pH were plotted on the VGA screen, permitting immediate evaluation of cell viability and the effects of treatments on [Ca2+]j and pHi. The experiments were also recorded on 3/4 inch U-matic video tape as a backup and to allow analysis of other cells in the video field since the same data display and data extraction procedures could be applied offline. Correction of [Ca2+]j, using the prevailing intracellular pH, standardization, data reduction analysis, and statistical methods has been previously described (Morris et al., 1994, In: Nuccitelli R (ed.) A Practical Guide to the Study of Ca 2 + in Living Cells. Meth. Cell. Biol. 40: 183-220). K + -depolarization of mIL cells results in a two phase increase in [Ca 2+ ]i. The fast phase, which peaks within about 10 sec, is due to influx through high voltage activated Ca2+ channels. A second slower phase, with a lower amplitude that peaks much later (30-60 sec), is due to release from intracellular stores. Therefore the change in Ca2+ level due to membrane channel activity was measured as: Percent change in [Ca2+]j = (Max Ca2+ - Min Ca2+ )/(Min Ca2+ x 100), where Max Ca2+ = (maximal [Ca2+]i value achieved within 10 sec following depolarization; Min Ca2+ = initial resting [Ca2+]i). EXAMPLE 9 Electrophysiology and calcium imaging of hippocampal neurons in brain slices Experiments were performed on CA1 pyramidal neurons in 300 μm thick hippocampal slices from 25-28 day old male Sprague-Dawley rats (Nurse & Lacaille, 1999, Neuropharmacol. 38:1733-1742). Slices were allowed to recover for at least one hour before use. The recording chamber was continuously perfused with oxygenated (95% O2 5% CO2) artificial cerebrospinal fluid (aCSF) containing (in mM) 124 NaCl, 2.5 KCl, 2.5 CaCl2, 26 NaHCO3, 1.25 NaH2PO4, 2 MgSO4, 10 glucose, pH 7.35-7.4. Experiments were conducted in the presence of 0.5μM tetrodotoxin (TTX) to block voltage-dependent Na+ channels. To block K + channels in the recorded neuron, patch pipettes (4-8 MΩ) were filled with a Cs-based solution containing (in mM) 140 CsMeSO3, 1 MgCl2, 5 NaCl, 2 ATP, 0.4 GTP, 10 HEPES and 100 μM of the Ca2+ indicator Oregon Green BAPTA-I (Molecular Probes, Eugene OR USA), titrated with CsOH to pH 7.25-7.28. Combined whole cell current- clamp recordings and confocal calcium imaging were performed from CA1 pyramidal neurons using an Axopatch 200B amplifier (Axon Instrument, Foster City, CA) and a multi-photon confocal laser scanning microscope (Zeiss, LSM 510) equipped with a 40x long-range water-immersion objective (numerical aperture 0.8). After obtaining the whole-cell configuration, at least 20 min were allowed for intracellular diffusion of the fluorophore. For two-photon confocal imaging, a tunable mode-locked Ti:Sapphire laser at 780 nm was used (5W Verdi argon ion laser and Mira 900, Coherent). Emission was detected through a long-pass filter (cut-off 505 nm) and recorded to a PC using the LSM 510 software (Zeiss). The confocal aperture was opened fully. Linescans were taken from the soma at a rate of 3.8 ms per line for a total scan time of 12 s (Figure 5A1). Pyramidal cells were activated by somatic depolarizing current injections via the recording pipette (Figure 5A2). Series resistance were monitored and compensated throughout the experiments. For linescans, the fluorescence intensity (Fjine) was averaged over the region of interest of the line across the cell soma. Changes in fluorescence were calculated for each line relative to the averaged baseline fluorescence prior to stimulation (F re st) and expressed as: %ΔF/F = [(Fjine - Frest)/ Frest] x 100. The values were then processed with a low-pass digital filter to remove fast transients (Igor Pro, Wavemetrics, Lake Oswego, OR) and the peak calcium response was determined for each linescan. Linescans and electrophysiological recordings were initiated manually. To compensate for small variations in the start time of the linescans, electrophysiological and Ca2+ responses were temporally aligned by eye (Figure 5A2). EXAMPLE 10 Statistical analysis The level of significance for differences between means was measured by Fisher's test, or analysis of variance (ANOVA) followed by the Bonferroni post- test (GraphPad InStat, San Diego, CA). EXAMPLE 11 Gabapentin inhibits VD-CCs in a melanotroph cell line Figure 11A shows typical changes in intracellular Ca2+ levels of individual mIL cells in response to depolarization by high extracellular K+ concentration. There is a sharp and major increase in [Ca2+]j attributed to the depolarization and activation of the VD-CCs followed by a slower second peak or shoulder due to release from intracellular stores consistent with previous findings in melanotropes (Morris et al., 1998, J. Neurochem. 71: 1329-1332). Figure 11B shows that the prototypical nonselective GABAB receptor agonist baclofen (1 μM) reduces the primary Ca2+ response. Figure 11C shows that baclofen effects are reversed by addition of the GABAB receptor antagonist CPG55845 (3 μM) (compare top middle and right panels). CPG55845 has no significant effect on the response to depolarization (compare Figures 11A and 11C). Figure 11D shows that 1 μM gabapentin action is nearly identical to 1 μM baclofen (compare to Figure 1 IB). The gabapentin effect is also completely blocked by 3 μM CGP55845 (compare Figures 11D and HE). Figure 12 shows the dose response curve for gabapentin inhibition of K+-evoked calcium mobilization with an EC502 μM and 70-80% of the total channel activity inhibited at 1 mM. Figure 13 shows that the VD-CC dependent rise in intracellular Ca2+, is blocked by 1 μM gabapentin, and that the gabapentin activity could be blocked completely and in a dose-dependent manner (30 nM-3 μM) by the GABAβ receptor antagonist CGP55845. Gabapentin inhibition of calcium mobilization was similar in magnitude (70-80%) and potency to baclofen (EC50 1 μM) suggesting that gabapentin actions were mediated by binding to the native gbla heteromer. To confirm that the inhibition of calcium mobilization owed to selective activation of the endogenous gbla heteromer and not to an activity of gabapentin on the endogenous VD-CC (e.g., binding to the α2δ subunit), we tested whether ADN treatment could selectively abolish the effect of gabapentin on K+- evoked increase in intracellular Ca2+. mUL cells were treated for 4 days with either gbla or gblb ADNs or a gbla mis-sense targeting sequence (see Example 7). These conditions were identical to the conditions used in previous studies which demonstrated that selective knockdown of either gbl or gb2 subunits but not mis-sense control antisense led to a selective reduction in protein expression of the targeted gene product, and in both cases a complete loss of GABAβ receptor-initiated reduction in VD-CC function. In this series of experiments, 10 and 30 μM gabapentin mediated 70-80% inhibition of the total K+-evoked VD-CC activity (Figure 14, compare A to B and C). Antisense knock-down of gbla in mIL cells was accompanied by a complete block of 10 and 30 μM gabapentin activity (Figure 14, compare columns B and C to E and F). In contrast, treatment with gblb ADN or the gbla mis-sense nucleotide was without effect on both 10 and 30 μM concentrations of gabapentin (compare columns B and C to H and I, K and L respectively). Taken together this demonstrated that gabapentin inhibition of calcium mobilization in mIL cells was due to activation of gabapentin- sensitive endogenously expressed gbla-gb2 heteromers. EXAMPLE 12 Gabapentin inhibition of VD-CCs via neuronal GABAB receptors in rat hippocampal neurons in situ To confirm stimulation by gabapentin at neuronal GABAB receptors coupled to VD-CCs in situ, we combined whole cell current clamp recordings of pyramidal cells with multiphoton confocal calcium imaging (Figure 15A1-2) and examined the effects of gabapentin on calcium responses evoked by somatic current injections in CA1 pyramidal neurons of rat hippocampal slices. In the presence of TTX and a K+ channel blocker (intracellular Cs), positive current pulses were applied to the pyramidal cell soma via the recording electrode and the evoked calcium responses were recorded electrophysiologically (membrane potential) and optically (fluorescence) (Figure 15A2). The amplitude of the current pulse was varied to elicit Ca2+ responses by sub-threshold stimulation (Figure 15B1 and 15C1) and Ca2+ spikes by supra-threshold stimulations (Figure 15B2 and 15C2). Sub-threshold current injections induced Ca2+ responses of small amplitude and short duration (Figure 15B1 and 15C1), whereas supra-threshold current injections triggered larger and longer-lasting Ca 2+ responses (Figure 15B2, 15C2) at the cell soma. In our experimental conditions, these responses induced by somatic current injection were solely mediated by Ca2+ since they were totally blocked in Ca 2+ -free aCSF (n=2 cells, data hot shown). For a given sub-threshold current injection, the membrane depolarization and its associated Ca + response (traces 1 in Figure 15B1) were significantly depressed in presence of 1 mM gabapentin (traces 2 in Figure 15B1). These effects of gabapentin were reversible (data not shown). When the current pulse amplitude was adjusted to elicit a Ca2+ spike in the pyramidal cell (traces 1 in Figure 15B2), the same current pulse in presence of gabapentin (lmM) failed to induce a Ca2+ spike (traces 2 in Figure 15B2) and solely evoked a subthreshold depolarization and a very small Ca2+ response. However, cells were still capable of producing Ca2+ spikes in the presence of gabapentin, since larger current injections induced a Ca2+ spike and its associated large and long-lasting Ca2+ response at the cell soma (traces 3 in Figure 15B2). Both the peak amplitude of the Ca2+ spike and Ca2+ response elicited by the larger stimulation in the presence of gabapentin were not significantly different from those in control conditions (76.3±4.7mV and 165.3±27% ΔF/F in gabapentin vs 82.9±3mV and 218.7+24% ΔF/F in control respectively, n=4, Figure 15B2). As observed for gabapentin, baclofen (40 μM) depressed in a reversible manner the membrane depolarizations and Ca2+ responses induced by both sub- and supra-threshold somatic current injections (Figure 15C). As for gabapentin, increasing the somatic current injection in the presence of baclofen restored both Ca2+ spikes and Ca2+ responses to levels similar to those in control (71.9±5.6mV and 167.9±61.4% ΔF/F in baclofen vs 76.9±2.5mV and 254.1±28.6% ΔF/F in control conditions; n=3, Figures 15C2 and 16D). The inhibition of Ca2+ responses by gabapentin was dose-dependent. The graphs on Figure 16A-B show the effects of different concentrations of gabapentin (100 μM to 1 mM) on membrane depolarizations and Ca2+ responses evoked by sub- and supra-threshold current injections. To test if the inhibitory action of gabapentin on Ca2+ responses was mediated by activation of GAB Aβ receptors, we investigated the effect of the GABAβ receptor antagonist CGP55845 on gabapentin actions. Gabapentin (2 mM) significantly reduced membrane depolarizations and Ca2+ responses evoked by both sub- and supra-threshold soma current injections (Figure 17C and D). This depressant effect of gabapentin was blocked in the presence of 4 μM CGP55845, for both sub- (Figure 17A1 and C) and supra-threshold (Figure 17A2 and D) current injections. Similarly, the inhibition of Ca2+ responses by baclofen was also blocked by CGP55845 (Figure 17B-D). These results indicate that gabapentin negatively couples to VD-CCs via GABAB receptors in hippocampal pyramidal neurons in situ. Taken together with the selective activation demonstrated for gabapentin at the endogenous brain GABAB receptor in mIL cells, our results suggest that one possible mechanism by which gabapentin exerts its CNS therapeutic actions is by a selective activation of neuronal gbla-gb2 GABAβ receptor heterodimers coupled to VD-CCs. The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

Claims: WHAT IS CLAIMED: 1. A method of identifying gb 1 a subtype-specific agonists of the GABAβ receptor that comprises (a) determining that a substance is an agonist of GABAB receptors comprising a gbla subunit; and (b) determining that the substance is not an agonist of GAB Aβ receptors comprising a gblb or gblc subunit. 2. The method of claim 1 that furthermore comprises one or more of the following steps: (c) determining that the substance activates post-synaptic potassium currents; (d) determining that the substance does not presynaptically depress GABA inhibitory postsynaptic currents; (e) determining that the substance is not an agonist of GABAA receptors; (f) determining that the substance is an agonist of GABAB receptors that are negatively coupled to voltage dependent-calcium channels. 3. A method of identifying a substance that is a gbla subtype- specific binding substance comprising: (a) exposing a substance, separately, to gbla cells, gblb cells, and gblc cells; (b) quantitating the binding of the substance to the gbla cells, gblb cells, and gblc cells; where, if the amount of binding of the substance to the gbla cells is at least 3 times greater than the amount of binding of the substance to both gblb and gblc cells, then the substance is a gbla subtype-specific binding substance. 4. The method of claim 3 where the gbla cells comprise an expression vector encoding gb2 and an expression vector encoding gbla and the cells are cultured under conditions such that gb2 and gbla are expressed and gbla heteromers are formed. 5. The method of claim 5 where: the gblb cells comprise an expression vector encoding gb2 and an expression vector encoding gblb and the gblb cells are cultured under conditions such that gb2 and gblb are expressed and gblb heteromers are formed; and the gblc cells comprise an expression vector encoding gb2 and an expression vector encoding gblc and the gblc cells are cultured under conditions such that gb2 and gblc are expressed and gblc heteromers are formed. 6. The method of claim 3, 4, or 5 that further comprises determining whether the gbla subtype-specific binding substance activates a functional response of a gbla receptor. 7. A method for identifying gbla subtype-specific binding substances that comprises: (a) providing gbla cells; (b) exposing the cells to gabapentin or pregabalin in the presence and in the absence of a substance; (c) measuring the binding of gabapentin or pregabalin to the gbla heteromers in the presence and in the absence of the substance; where, if the amount of binding of gabapentin or pregabalin is less in the presence of the substance than in the absence of the substance, then; (d) determining whether the substance binds to gblb cells and gblc cells; where, if the substance does not bind to gblb cells and gblc cells, then the substance is a gbla subtype-specific binding substance. 8. The method of claim 7 where the gbla cells comprise an expression vector encoding gb2 and an expression vector encoding gbla and the cells are cultured under conditions such that gb2 and gbla are expressed and gbla heteromers are formed. 9. The method of claim 8 where: the gblb cells comprise an expression vector encoding gb2 and an expression vector encoding gblb and the gblb cells are cultured under conditions such that gb2 and gblb are expressed and gblb heteromers are formed; and the gblc cells comprise an expression vector encoding gb2 and an expression vector encoding gblc and the gblc cells are cultured under conditions such that gb2 and gblc are expressed and gblc heteromers are formed. 10. The method of claim 7, 8, or 9 that further comprises determining whether the gbla subtype-specific binding substance activates a functional response of a gb 1 a receptor. 11. A method for identifying a gbla subtype-specific agonist of the GABAβ receptor comprising: (a) providing a Xenopus laevis oocyte expressing gbla and gb2 so as to form a functional gbla heteromer in the oocyte where the oocyte also expresses a Kir; (b) exposing the oocyte of step (a) to a substance while monitoring potassium ion flow across the oocyte membrane; (c) providing a Xenopus laevis oocyte expressing gblb and gb2 so as to form a functional gblb heteromer in the oocyte where the oocyte also expresses a Kir; (d) exposing the oocyte of step (c) to the substance while monitoring potassium ion flow across the oocyte membrane; (e) providing a Xenopus laevis oocyte expressing gblc and gb2 so as to form a functional gblc heteromer in the oocyte where the oocyte also expresses a Kir; (f) exposing the oocyte of step (e) to the substance while monitoring potassium ion flow across the oocyte membrane; where if the exposure of the oocytes to the substance results in increased potassium ion flow in step (b) but not in steps (d) and (f) then the substance is a gbla subtype-specific agonist of the GABAB receptor. 12. The method of claim 11 where: (i) the oocytes of step (a) have been microinjected with RNA encoding gbla, gb2, and a Kir; (ii) the oocytes of step (c) have been microinjected with RNA encoding gblb, gb2, and a Kir; (iii) the oocytes of step (e) have been microinjected with RNA encoding gblc, gb2, and a Kir. 13. The method of claim 12 where the monitoring of steps (b), (d), and (f) is done by patch clamp recordings. 14. A method for identifying a gbla subtype-specific agonist that comprises: (a) determining whether a substance activates a GABAβ receptor functional response in gbla cells; (b) determining whether the substance activates a GABAB receptor functional response in gblb cells; (c) determining whether the substance activates a GABAB receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in the gbla cells, but not in the gblb or gblc cells, then the substance is a gbla subtype-specific agonist. 15. The method of claim 14 where the functional response is a decrease in intracellular calcium levels. 16. The method of claim 15 where the decrease in intracellular calcium levels is measured by the use of a calcium indicator dye. 17. The method of claim 16 where the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1.. 18. A method for identifying gbla subtype-specific agonists comprising: (a) providing gbla cells; (b) loading the gbla cells with a calcium indicator dye; (c) measuring a fluorescence characteristic of the calcium indicator dye in the gbla cells in the presence and in the absence of a substance; (d) providing gb 1 b cells ; (e) loading the gblb cells with a calcium indicator dye; (f) measuring a fluorescence characteristic of the calcium indicator dye in the gblb cells in the presence and in the absence of the substance; (g) providing gblc cells; (h) loading the gblc cells with a calcium indicator dye; (i) measuring a fluorescence characteristic of the calcium indicator dye in the gblc cells in the presence and in the absence of the substance; where if a change in fluorescent characteristic in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) and step (i) then the substance is a gbla subtype-specific agonist. 19. The method of claim 18 where the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. 20. The method of claim 18 or 19 where the change in fluorescent characteristic is an increase in intensity of a fluorescence emission maximum, a shift in the wavelength of an emission maximum, or a shift in the wavelength of an absorption maximum. 21. A method for identifying a gbla subtype-specific agonist that comprises: (a) determining whether a substance activates a GABAB receptor functional response in a melanotroph cell line that express gbla receptors but not gblb receptors or gblc receptors; (b) determining whether the substance activates a GAB Aβ receptor functional response in gblb cells; (c) determining whether the substance activates a GAB Aβ receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in the melanotroph cell line, but not in the gblb or gblc cells, then the substance is a gbla subtype-specific agonist. 22. The method of claim 21 where the melanotroph cell line is selected from the group consisting of mIL39 cells and mIL-tsA58 cells. 23. The method of claim 21 or 22 where the functional response is selected from the group consisting of: modulation of the activity of an ion channel; changes in calcium concentration; changes in a signal from a reporter gene whose expression is controlled by a promoter that is induced by interaction of an agonist with the GABAβ receptor; and changes in membrane currents. 24. The method of claim 23 where the change in membrane current is caused by the modulation of the activity of an inwardly rectifying potassium current or the modulation of the activity of a voltage dependent-calcium channel. 25. The method of claim 21 where the gblb cells and gblc cells are cells that do not naturally express any GABAB receptor subunits and have been transfected with expression vectors encoding gblb or gblc subunits as well as gb2 subunits so as to form functional gblb or gblc receptors. 26. A method for identifying gbla subtype-specific agonists comprising: (a) providing gbla cells that express apoaequorin; (b) loading the gbla cells with coelenterazine so that aequorin is formed in the gbla cells; (c) measuring the emission of light caused by the interaction of calcium and the aequorin in the gbla cells in the presence and in the absence of a substance; (d) providing gblb cells that express apoaequorin; (e) loading the gblb cells with coelenterazine so that aequorin is formed in the gblb cells; (f) measuring the emission of light caused by the interaction of calcium and the aequorin in the gblb cells in the presence and in the absence of the substance; (g) providing gblc cells that express apoaequorin; (h) loading the gblc cells with coelenterazine so that aequorin is formed in the gblc cells; (i) measuring the emission of light caused by the interaction of calcium and the aequorin in the gblc cells in the presence and in the absence of the substance; where if less light emission in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) and step (i) then the substance is a gbla subtype-specific agonist. 27. A method of identifying substances that are specific for the gbla heteromer as opposed to the gblb heteromer that comprises (a) determining that a substance is an agonist of GAB Aβ receptors comprising a gbla subunit; and (b) determining that the substance is not an agonist of GAB Aβ receptors comprising a gblb subunit. 28. The method of claim 27 furthermore comprising one or more of the following steps: (c) determining that the substance activates post-synaptic potassium currents; (d) determining that the substance does not presynaptically depress GABA inhibitory postsynaptic currents; (e) determining that the substance is not an agonist of GAB AA receptors; (f) determining that the substance is an agonist of GAB Aβ receptors that are negatively coupled to voltage dependent-calcium channels. 29. A method of identifying substances that are specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) exposing a substance, separately, to gbla cells and gblb cells; (b) quantitating the binding of the substance to the gbla cells and gblb cells; where, if the amount of binding of the substance to the gbla cells is at least 3 times greater than the amount of binding of the substance to the gblb cells, then the substance is specific for the gbla heteromer as opposed to the gblb heteromer. 30. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer that comprises: (a) providing gb 1 a cells ; (b) exposing the gbla cells to gabapentin or pregabalin in the presence and in the absence of a substance; (c) measuring the binding of gabapentin or pregabalin to the gbla heteromers in the presence and in the absence of the substance; where, if the amount of binding of gabapentin or pregabalin in step (c) is less in the presence of the substance than in the absence of the substance, then; (d) determining whether the substance binds to gblb cells; where, if the substance does not bind to gblb cells, then the substance is a substance that is specific for the gbla heteromer as opposed to the gblb heteromer. 31. The method of claim 30 where the gbla cells comprise an expression vector encoding gb2 and an expression vector encoding gbla and the gbla cells are cultured under conditions such that gb2 and gbla are expressed and gbla heteromers are formed; and the gblb cells comprise an expression vector encoding gb2 and an expression vector encoding gblb and the gblb cells are cultured under conditions such that gb2 and gblb are expressed and gblb heteromers are formed. 32. The method of claim 31 further comprising determining whether the substance that is specific for the gbla heteromer as opposed to the gblb heteromer activates a functional response of a gbla receptor. 33. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) providing a Xenopus laevis oocyte expressing gbla and gb2 so as to form a functional gbla heteromer in the oocyte where the oocyte also expresses a Kir; (b) exposing the oocyte of step (a) to a substance while monitoring potassium ion flow across the oocyte membrane; (c) providing a Xenopus laevis oocyte expressing gblb and gb2 so as to form a functional gblb heteromer in the oocyte where the oocyte also expresses a Kir; (d) exposing the oocyte of step (c) to the substance while monitoring potassium ion flow across the oocyte membrane; where if the exposure of the oocytes to the substance results in increased potassium ion flow in step (b) but not in step (d) then the substance is a substance that is specific for the gbla heteromer as opposed to the gblb heteromer. 34. The method of claim 33 where: (i) the oocytes of step (a) have been microinjected with RNA encoding gbla, gb2, and a Kir; (ii) the oocytes of step (c) have been microinjected with RNA encoding gblb, gb2, and a Kir. 35. The method of claim 34 where the monitoring of steps (b) and (d) is done by patch clamp recordings. 36. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) determining whether a substance activates a GABAB receptor functional response in gbla cells; (b) determining whether the substance activates a GAB Aβ receptor functional response in gblb cells; where if the substance activates a GAB Aβ receptor functional response in gbla cells, but not in gblb, then the substance is specific for the gbla heteromer as opposed to the gblb heteromer. 37. The method of claim 36 where the functional response is a decrease in intracellular calcium levels. 38. The method of claim 37 where the decrease in intracellular calcium levels is measured by the use of a calcium indicator dye. 39. The method of claim 38 where the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. 40. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) providing gbla cells; (b) loading the gbla cells with a calcium indicator dye; (c) measuring a fluorescence characteristic of the calcium indicator dye in the gbla cells in the presence and in the absence of a substance; (d) providing gblb cells; (e) loading the gblb cells with a calcium indicator dye; (f) measuring a fluorescence characteristic of the calcium indicator dye in the gblb cells in the presence and in the absence of the substance; where if a change in fluorescent characteristic in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) then the substance is a substance that is specific for the gbla heteromer as opposed to the gblb heteromer. 41. The method of claim 40 where the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. 42. The method of claim 40 where the change in fluorescent characteristic is an increase in intensity of a fluorescence emission maximum, a shift in the wavelength of an emission maximum, or a shift in the wavelength of an absorption maximum. 43. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer that comprises: (a) determining whether a substance activates a GABAβ receptor functional response in a melanotroph cell line that express gbla receptors but not gblb receptors; (b) determining whether the substance activates a GABAβ receptor functional response in gblb cells; where if the substance activates a GAB Aβ receptor functional response in the melanotroph cell line, but not in the gblb, then the substance is specific for the gbla heteromer as opposed to the gblb heteromer. 44. The method of claim 43 where the melanotroph cell line is selected from the group consisting of mIL39 cells and mIL-tsA58 cells. 45. The method of claim 43 where the functional response is selected from the group consisting of: modulation of the activity of an ion channel; changes in calcium concentration; changes in a signal from a reporter gene whose expression is controlled by a promoter that is induced by interaction of an agonist with the GABAB receptor; and changes in membrane currents. 46. The method of claim 45 where the change in membrane current is caused by the modulation of the activity of an inwardly rectifying potassium current or the modulation of the activity of a voltage dependent-calcium channel. 47. The method of claim 43 where the gblb cells are cells that do not naturally express any GABAB receptor subunits and have been transfected with expression vectors encoding gblb subunits as well as gb2 subunits so as to form functional gblb receptors. 48. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblb heteromer comprising: (a) providing gbla cells that express apoaequorin; (b) loading the gbla cells with coelenterazine so that aequorin is formed in the gbla cells; (c) measuring the emission of light caused by the interaction of calcium and the aequorin in the gbla cells in the presence and in the absence of a substance; (d) providing gblb cells that express apoaequorin; (e) loading the gblb cells with coelenterazine so that aequorin is formed in the gblb cells; (f) measuring the emission of light caused by the interaction of calcium and the aequorin in the gblb cells in the presence and in the absence of the substance; where if less light emission in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) then the substance is specific for the gbla heteromer as opposed to the gblb heteromer. 49. A method of identifying substances that are specific for the gbla heteromer as opposed to the gblc heteromer that comprises (a) determining that a substance is an agonist of GABAB receptors comprising a gbla subunit; and (b) determining that the substance is not an agonist of GAB Aβ receptors comprising a gblc subunit. 50. The method of claim 49 further comprising one or more of the following steps: (c) determining that the substance activates post-synaptic potassium currents; (d) determining that the substance does not presynaptically depress GABA inhibitory postsynaptic currents; (e) determining that the substance is not an agonist of GAB AA receptors; (f) determining that the substance is an agonist of GABAβ receptors that are negatively coupled to voltage dependent-calcium channels. 51. A method of identifying substances that are specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) exposing a substance, separately, to gbla cells and gblc cells; (b) quantitating the binding of the substance to the gbla cells and gblc cells; where, if the amount of binding of the substance to the gbla cells is at least 3 times greater than the amount of binding of the substance to the gblc cells, then the substance is specific for the gbla heteromer as opposed to the gblc heteromer. 52. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer that comprises: (a) providing gbla cells; (b) exposing the gbla cells to gabapentin or pregabalin in the presence and in the absence of a substance; (c) measuring the binding of gabapentin or pregabalin to the gbla heteromers in the presence and in the absence of the substance; where, if the amount of binding of gabapentin or pregabalin in step (c) is less in the presence of the substance than in the absence of the substance, then; (d) determining whether the substance binds to gblc cells; where, if the substance does not bind to gblc cells, then the substance is a substance that is specific for the gbla heteromer as opposed to the gblc heteromer. 53. The method of claim 52 where: the gbla cells comprise an expression vector encoding gb2 and an expression vector encoding gbla and the gbla cells are cultured under conditions such that gb2 and gbla are expressed and gbla heteromers are formed; and the gblc cells comprise an expression vector encoding gb2 and an expression vector encoding gblc and the gblc cells are cultured under conditions such that gb2 and gblc are expressed and gblc heteromers are formed. 54. The method of claim 49, 51, or 52 further comprising determining whether the substance that is specific for the gbla heteromer as opposed to the gblc heteromer activates a functional response of a gbla receptor. 55. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) providing a Xenopus laevis oocyte expressing gbla and gb2 so as to form a functional gbla heteromer in the oocyte where the oocyte also expresses a Kir; (b) exposing the oocyte of step (a) to a substance while monitoring potassium ion flow across the oocyte membrane; (c) providing a Xenopus laevis oocyte expressing gblc and gb2 so as to form a functional gblc heteromer in the oocyte where the oocyte also expresses a Kir; (d) exposing the oocyte of step (c) to the substance while monitoring potassium ion flow across the oocyte membrane; where if the exposure of the oocytes to the substance results in increased potassium ion flow in step (b) but not in step (d) then the substance is a substance that is specific for the gbla heteromer as opposed to the gblc heteromer. 56. The method of claim 55 where: (i) the oocytes of step (a) have been microinjected with RNA encoding gbla, gb2, and a Kir; (ii) the oocytes of step (c) have been microinjected with RNA encoding gblc, gb2, and a Kir. 57. The method of claim 55 or 56 where the monitoring of steps (b) and (d) is done by patch clamp recordings. 58. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) determining whether a substance activates a GABAβ receptor functional response in gbla cells; (b) determining whether the substance activates a GAB Aβ receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in gbla cells, but not in gblc, then the substance is specific for the gbla heteromer as opposed to the gblc heteromer. 59. The method of claim 58 where the functional response is a decrease in intracellular calcium levels. 60. The method of claim 59 where the decrease in intracellular calcium levels is measured by the use of a calcium indicator dye. 61. The method of claim 60 where the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. 62. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) providing gb 1 a cells ; (b) loading the gbla cells with a calcium indicator dye; (c) measuring a fluorescence characteristic of the calcium indicator dye in the gbla cells in the presence and in the absence of a substance; (d) providing gblc cells; (e) loading the gblc cells with a calcium indicator dye; (f) measuring a fluorescence characteristic of the calcium indicator dye in the gblc cells in the presence and in the absence of the substance; where if a change in fluorescent characteristic in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) then the substance is a substance that is specific for the gbla heteromer as opposed to the gblc heteromer. 63. The method of claim 62 where the calcium indicator dye is selected from the group consisting of: fluo-3, fura-2, fluo-4, fluo-5, aequorin, calcium green-1, Oregon green, 488 BAPTA, SNARF-1, and indo-1. 64. The method of claim 62 where the change in fluorescent characteristic is an increase in intensity of a fluorescence emission maximum, a shift in the wavelength of an emission maximum, or a shift in the wavelength of an absorption maximum. 65. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer that comprises: (a) determining whether a substance activates a GABAB receptor functional response in a melanotroph cell line that express gbla receptors but not gblc receptors; (b) determining whether the substance activates a GAB Aβ receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in the melanotroph cell line, but not in the gblc cells, then the substance is specific for the gbla heteromer as opposed to the gblc heteromer. 66. The method of claim 65 where the melanotroph cell line is selected from the group consisting of mIL39 cells and mIL-tsA58 cells. 67. The method of claim 65 where the functional response is selected from the group consisting of: modulation of the activity of an ion channel; changes in calcium concentration; changes in a signal from a reporter gene whose expression is controlled by a promoter that is induced by interaction of an agonist with the GABAβ receptor; and changes in membrane currents. . 68. The method of claim 67 where the change in membrane current is caused by the modulation of the activity of an inwardly rectifying potassium current or the modulation of the activity of a voltage dependent-calcium channel. 69. The method of claim 67 where the gblc cells are cells that do not naturally express any GABAB receptor subunits and have been transfected with expression vectors encoding gblc subunits as well as gb2 subunits so as to form functional gblc receptors. 70. A method for identifying a substance that is specific for the gbla heteromer as opposed to the gblc heteromer comprising: (a) providing gbla cells that express apoaequorin; (b) loading the gbla cells with coelenterazine so that aequorin is formed in the gbla cells; (c) measuring the emission of light caused by the interaction of calcium and the aequorin in the gbla cells in the presence and in the absence of a substance; (d) providing gblc cells that express apoaequorin; (e) loading the gblc cells with coelenterazine so that aequorin is formed in the gblc cells; (f) measuring the emission of light caused by the interaction of calcium and the aequorin in the gblc cells in the presence and in the absence of the substance; where if less light emission in the presence as compared to the absence of the substance is measured in step (c) but not in step (f) then the substance is specific for the gbla heteromer as opposed to the gblc heteromer. 71. A method for identifying a substance that is a gblb subtype- specific agonist comprising: (a) determining whether a substance activates a GABAB receptor functional response in gbla cells; (b) determining whether the substance activates a GAB Aβ receptor functional response in gblb cells; (c) determining whether the substance activates a GABAB receptor functional response in gblc cells; where if the substance activates a GABAβ receptor functional response in the gblb cells, but not in the gbla or gblc cells, then the substance is a gblb subtype-specific agonist. 72. A method for identifying a substance that is a gblc subtype- specific agonist comprising: (a) determining whether a substance activates a GABAβ receptor functional response in gbla cells; (b) determining whether the substance activates a GAB Aβ receptor functional response in gblb cells; (c) determining whether the substance activates a GAB Aβ receptor functional response in gblc cells; where if the substance activates a GAB Aβ receptor functional response in the gblc cells, but not in the gbla or gblb cells, then the substance is a gblc subtype-specific agonist.

Inventors: NG GORDON, NG, GORDON
Applicants: MERCK FROSST CANADA INC, NG GORDON, MERCK FROSST CANADA & CO., NG, GORDON
Application year: 2001
Main classification: G01N33
IPC codes: C12N15, C12Q1, G01N21, G01N31, G01N33