bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological and morphological properties of accumbens core and shell neurons recorded in vitro
Authors: O'Donnell Patricio , Grace Anthony A.
Published: December 2004

The morphology and electrophysiological properties of neurons in the nucleus accumbens were studied using intracellular recording techniques in rat brain slices maintained in vitro. Neurons were subdivided according to their location in the shell or core region of the nucleus accumbens. Most of the cells in both regions had small to medium‐sized (15.8 ± 2.8 μM) somata with densely spinous dendrites, somewhat similar to the striatal medium spiny neuron. However, minor morphological differences between neurons from accumbens core and shell regions were found, such as fewer primary dendrites in shell neurons than in the core (3.8 ± 0.8 vs. 4.4 ± 1.0) and the spatial organization of their dendritic trees. In general, the passive membrane properties of neurons in each region were similar. However, shell neurons appeared to be less excitable in nature, as suggested by (1) a faster time constant, (2) the absence of TTX‐insensitive events resembling low‐threshold spikes, and (3) the lower probability of evoking spikes in shell neurons by stimulation of amygdaloid or cortical afferents in comparison to the responses of coreneurons to cortical afferent stimulation. In most nucleus accumbens neurons the action potentials evoked by membrane depolarization were preceded by a slow Ca2+‐dependent depolarization and showed firing‐frequency adaptation. Following TTX administration, all‐or‐none spike‐like events resembling high‐threshold calcium spikes were observed in both regions. In summary, except for minor differences, most of the properties of core and shell neurons are similar, supporting their characterization as subdivisions of a single structure. Therefore, differences in the functional properties of these neuronal populations are likely to be due to their distinct connectivity patterns. © 1993 Wiley‐Liss, Inc.
Behavioral indices of moderate nigro‐striatal 6‐hydroxydopamine lesion: A preclinical Parkinson's model
Authors: Fornaguera J. , Schwarting R. K. W. , Boix F. , Huston J. P.
Published: December 2004

Asymmetries in turning and scanning were investigated in rats with different degrees of neostriatal dopamine depletion after unilateral injections of 6‐hydroxydopamine into the substantia nigra. Animals with severe lesions, i. e., residual dopamine levels of <20%, spontaneously turned ipsiversive and showed more scanning behavior with the side ipsilateral to the lesion. These asymmetries were reversed by the dopamine receptor agonist apomorphine. Animals with less severe dopamine depletion, i. e., residual dopamine levels of 20–65%, did not show an asymmetry in spontaneous turning, but an ipsilateral asymmetry in scanning was still observed, indicating a greater sensitivity of this measure for moderate striatal dopamine depletions. Furthermore, in animals with residual dopamine levels of 45–65%, the dopamine receptor agonist apomorphine did not lead to a behavioral reversal as with severe lesions, but induced ipsilateral scanning and ipsiversive turning. These ipsiversive asymmetries are discussed in relation to asymmetries in self‐regulatory mechanisms of the nigro‐striatal dopamine system, such as dopamine autoreceptors controlling the release of this transmitter. Dopamine receptor‐stimulated behavioral asymmetry in animals with moderate depletions of dopamine is suggested as a preclinical model to study mechanisms affected in the early state of Parkinson's disease. © 1993 Wiley‐Liss, Inc.
Long‐lasting potentiation of synaptic transmission in the schaffer collateral‐commissural pathway of the guinea pig hippocampus by activation of postsynaptic N‐methyl‐D‐aspartate receptor
Authors: Kamiya Haruyuki , Sawada Satsuki , Yamamoto Chosaburo
Published: December 2004

The effects of short‐period (2 min) perfusion of conditioning solution, which contains N‐methyl‐D‐aspartate (NMDA), glycine, and spermine, on the synaptic transmission in the Schaffer collateral‐commissural pathway were examined in hippocampal slices with the intracellular recording technique. Long‐lasting potentiation of excitatory postsynaptic potentials (EPSPs) was induced (as long as the records lasted, up to 3 h in the longest observation) after membrane potentials of postsynaptic neurons were depolarized by current injection during perfusion of the conditioning solution. D‐2‐amino‐5‐phoshonovaleric acid (D‐AP5), a specific antagonist of NMDA receptors, block the induction of the long‐lasting potentiation by perfusion of NMDA containing solution. This potentiation was accompanied by a decrease in the relative magnitude of EPSP amplitude fluctuation (coefficient of varation, CV). The reciprocals of squared CVs (= mean2/variance) were almost proportional to the magnitude of the potentiation, and the ratios of 1/CV2 and the magnitudes of potentiation were not different from those of long‐term potentiation (LTP) induced by tetanic stimulation. These findings suggest that long‐lasting potentiation is induced solely by activation of postsynaptic NMDA receptors, and transmitter release from presynaptic terminals may be modified by the activation of postsynaptic receptors. © 1993 Wiley‐Liss, Inc.
In vivo assessment of basal and drug‐induced dopamine release in cortical and subcortical regions of the anesthetized primate
Authors: Moghaddam Bita , Berridge Craig W. , Goldman‐Rakic Patricia S. , Bunney Benjamin S. , Roth Robert H.
Published: December 2004

There is an acute interest in studying the functional characteristics of dopamine systems in the cortex of primates. In particular, the prefrontal cortical dopamine projections have received a great deal of attention. This system is essential for proper functioning of the prefrontal cortex, and dysfunction within the system may be involved in some psychiatric and neurological illnesses. In vivo assessments of cortical dopamine in the primate have been scarce. This has been due, in part, to technical difficulties associated with these studies and with quantifying the relatively low levels of dopamine found in cortical regions. In the present study, intracerebral microdialysis was utilized to assess the extracellular concentration of dopamine in cortical and subcortical areas of the pentobarbital‐anesthetized rhesus monkey. Basal extracellular dopamine levels were consistently detected in the medial prefrontal cortex, premotor cortex, and caudate‐putamen. The basal extracellular concentration of dopamine in the dorsolateral prefrontal cortex was reliably detected in 1 of 4 animals. Intravenous administration of amphetamine (1 mg/kg) enhanced extracellular dopamine levels in the caudate‐putamen area by more than 20‐fold. In cortical areas, amphetamine's effect was less profound: An increase of 400–500 percent over basal extracellular dopamine levels was observed in each region. These studies demonstrate the feasibility of microdialysis for detecting extracellular fluxes of dopamine in the cortex of nonhuman primates. They further provide direct evidence that the dopamine released within the prefrontal cortex and the premotor cortex of nonhuman primates responds to pharmacological manipulation. © 1993 Wiley‐Liss, Inc.
SPECT imaging of dopamine and serotonin transporters with [123I]β‐CIT: Pharmacological characterization of brain uptake in nonhuman primates
Authors: Laruelle Marc , Baldwin Ronald M. , Malison Robert T. , Zea‐Ponce Yolanda , Zoghbi Sami S. , Al‐Tikeriti Mohammed S. , Sybirska Elzbieta H. , Zimmermann Ralph C. , Wisniewski Gary , Neumeyer John L. , Milius Richard A. , Wang Shaoyin , Smith Eileen O. , Roth Robert H. , Charney Dennis S. , Hoffer Paul B. , Innis Robert B.
Published: December 2004

Single photon emission computed tomography (SPECT) studies of regional kinetic uptake and pharmacological specificity of [123I] methyl 3β‐ (4‐iodophenyl) tropane‐2β‐carboxylate ([123I]β‐CIT) were performed in nonhuman primates (n = 41). In control experiments, activity was concentrated in striatum and in hypothalamic/midbrain regions. Striatal uptake increased for 140–180 min and displayed stable levels thereafter. Striatal to cerebellar activity rations were 7.3 ± 0.9 (mean ± SEM) at 300 min. About 75% of striatal uptake was displaceable by injection of nonradioactive β‐CIT. Hypothalamic/midbrain activity reached maximal levels at approximately 45 min. A slow washout phase followed this peak activity. Activities in frontal, occipital, and cerebellar regions were characterized by an early peak (20–30 min), followed by rapid washout. Displacement studies demonstrated that striatal uptake was associated with dopamine (DA) transporters, as it was displaced by GBR 12909, a selective DA uptake inhibitor, but not by citalopram, a selective serotonin (5‐HT) uptake inhibitor. The inverse was true in the hypothalamic/midbrain area, suggesting that the uptake in this area was associated primarily with 5‐HT transporters. Maprotiline, a selective norepinephrine uptake inhibitor, did not affect [123I]β‐CIT uptake. In vivo site occupancy ED50 values of cocaine, 2β‐carbomethoxy‐3β‐(4‐fluorophenyl) tropane (CFT), and β‐CIT were measured in the striatum with a stepwise displacement paradigm. In vivo ED50 values correlated strongly with in vitro IC50 values for binding to DA transporters. Infusion of high dose of L‐DOPA (250 μMol/kg) failed to displace striatal [123I]β‐CIT binding, suggesting that the binding would not be affected by L‐DOPA administration in Parkinsonian patients. However, studies performed with injection of d‐amphetamine indirectly suggested that high synaptic levels of DA may compete with [123I]β‐CIT binding, These studies suggest that [123I]β‐CIT will be a useful SPECT tracer of DA and 5‐HT transporters in living human brain. © 1993 Wiley‐Liss, Inc.
Molecular alterations in the neostriatum of human cocaine addicts
Authors: Hurd Yasmin L. , Herkenham Miles
Published: December 2004

Molecular changes in the neostriatum of human subjects who died with a history of cocaine abuse were revealed in discrete cell populations by means of the techniques of in situ hybridization histochemistry and in vitro receptor binding and autoradiography. Cocaine subjects had a history of repeated cocaine use and had cocaine and/or cocaine metabolites on board at the time of death. These subjects were compared to control subjects that had both a negative history and toxicology of cocaine use. Selective alterations in mRNA levels of striatal neuropeptides were detected in cocaine subjects compared to control subjects, especially for the opioid peptides. Marked reductions in the levels of enkephalin mRNA and μ opiate receptor binding were found in the caudate and putamen, concomitant with elevations in levels of dynorphin mRNA and κ opiate receptor binding in the putamen and caudate, respectively. Dopamine uptake site binding was reduced in the caudate and putamen of cocaine subjects. The greater magnitude of changes in the dorsolateral striatum (caudate and putamen) as opposed to the ventromedial striatum (nucleus accumbens) suggests that cocaine abuse preferentially alters the biosynthetic activity of striatal systems associated with sensorimotor functioning. Additionally, an imbalance in the activity of the two major striatal output pathways in cocaine users is implicated because peptide mRNA levels were reduced in enkephalinergic striatopallidal neurons and increased in dynorphinergic striatonigral neurons. Another imbalance, that of reductions of transmitter mRNA and receptor expression associated with euphoria (enkephalin and μ opiate receptors), together with elevations in mRNAs of transmitter systems associated with dysphoria (dynorphin and κ opiate receptors), suggests a model of dysphoria and craving in the human cocaine addict brain. © 1993 Wiley‐Liss, Inc.
Extracellular glutamate levels increase with age in the lateral striatum: Potential involvement of presynaptic D‐2 receptors
Authors: Donzanti Bruce A. , Hite Juliana F. , Yamamoto Bryan K.
Published: December 2004

In the lateral striatum of aged rats, dopamine D‐2 receptor density is reduced and glutamate tissue content is elevated. D‐2 receptor agonists have been shown to inhibit stimulated glutamate release. In the present study, microdialysis was used to investigate a potential role for D‐2 receptors in the modulation of striatal glutamate efflux from 4‐, 12‐, 18‐, and 24–26‐month‐old Fischer 344 rats. Extracellular basal glutamate concentrations significantly increased as a function of age in the lateral, but not medial, striatum. Neither the D‐2 agonist, LY 163502, nor the D‐2 antagonist, sulpiride, influenced basal glutamate efflux, suggesting that the dopaminergic system is not involved in the observed age‐related increase in extracellular basal glutamate levels. In contrast to basal efflux, potassium‐evoked glutamate release was not altered with age. However, LY 163502 significantly inhibited stimulated glutamate release in 4‐month‐old rats. This inhibitory action was not observed at any other age. Sulpiride alone did not alter stimulated glutamate release, but it did block the inhibitory effect of LY 163502 in the 4‐month‐old rats. These results provide in vivo evidence for an age‐related functional loss in the modulation of striatal glutamate release by dopamine D‐2 receptors in addition to increased basal glutamate efflux, which is not related to D‐2 receptor modulation. Such mechanisms could be important in the pathophysiology of striatal cell death during aging and age‐related neurodegenerative diseases. © 1993 Wiley‐Liss, Inc.
Identification of a GBR12935 homolog, LR1111, which is over 4,000‐fold selective for the dopamine transporter, relative to serotonin and norepinephrine transporters
Authors: Rothman Richard B. , Lewis Bruce , Dersch Chris , Xu Heng , Radesca Lillian , De Costa Brian R. , Rice Kenner C. , Kilburn Robert B. , Akunne Hyacinth C. , Pert Agu
Published: December 2004

The di‐substituted piperazines, GBR12909 (1‐[2‐[bis(4‐fluorophenyl)‐methoxy]ethyl]‐4‐[3‐phenylpropyl]piperazine) and GBR12935 (1‐[2‐(diphenyl‐methoxy)‐ethyl]‐4‐(3‐phenylpropyl)piperazine), are potent and selective (20‐to 100‐fold) inhibitors of [3H]dopamine reuptake, relative to [3H]5‐HT and [3H]norepinephrine uptake. The GBR12935 analog, 1‐(2‐(diphenylmethoxy)ethyl)‐4‐(3‐phenylpropyl)homopiperazine (LR1111), was synthesized as part of a systematic structure‐activity study of analogs of GBR12935 and GBR12909. LR1111 differs from GBR12935 by the addition of a methylene group into the piperazine ring to yield a compound with a seven‐member homopiperazine ring. The IC50 values for LR1111 at the dopamine, norepinephrine, and serotonin transporters were 7.2 nM, 34, 072 nM, and greater than 20,000 nM, respectively, whereas the IC50 values of GBR12935 were 3.7 nM, 289 nM, and 1261 nM for these same transporters. This demonstrates that the addition of a single methylene group in the piperazine ring results in a compound with similar affinity but significantly higher selectivity for the dopamine transporter. LR1111 increased motoric activity in rats after intravenous administration. These indicate that LR1111 is a potent and highly selective inhibitor of the dopamine transporter. Published 1993 Wiley‐Liss, Inc.
Differential pharmacological profile of striatal and cerebellar dopamine receptors labeled by [3H]quinpirole: Identification of a discrete population of putative D3 receptors
Authors: Levant Beth , De Souza Errol B.
Published: December 2004

We have previously identified [3H]quinpirole‐labeled dopamine receptors in the molecular layer of cerebellar lobule 10 which have a D2‐like pharmacological profile, are guanine nucleotide‐insensitive, and are juxtaposed to putative D3 receptor mRNA. This study compares the pharmacological profiles of [3H]quinpirole‐labeled dopamine receptors in striatum and cerebellar lobule 10 using quantitative autoradiography. Dopaminergic compounds inhibited the specific binding of [3H]quinpirole in the caudate/putamen with the following rank order of potencies: spiperone > haloperidol ≥ (+)butaclamol ≥ quinpirole ≥ 7‐OH‐DPAT ≥ bromocriptine > clozapine > (‐)sulpiride. In cerebellar lobule 10, a somewhat different rank order of potencies was observed: 7‐OH‐DPAT > quinpirole ≥ bromocriptine > spiperone > (+)butaclamol > haloperidol > clozapine > (‐)sulpiride. Quinpirole possessed equal affinity for [3H]quinpirole‐labeled receptors in the caudate/putamen and cerebellum. 7‐OH‐DPAT exhibited 5‐fold greater affinity for cerebellar receptors than those in the caudate/putamen. Spiperone, haloperidol, (+)butaclamol, and clozapine were more potent in competing for [3H]quinpirole binding at striatal dopamine receptors than cerebellar receptors by 83‐, 59‐, 11‐, and 6‐fold, respectively. The relative potencies of these compounds at striatal and cerebellar dopamine receptors are generally similar to the differential affinities reported at D2 and D3 dopamine receptors expressed in CHO cells, respectively. These data provide additional evidence that the dopamine receptors observed in cerebellar lobule 10 represent a discrete population of putative D3 receptors. © Wiley‐Liss, Inc.
Expression of adenosine A1 receptors in cultured neurons from fetal rat brain
Authors: Nicolas Frédéric , Daval Jean‐Luc
Published: December 2004

The expression of adenosine A1 receptors was investigated using [3H]2‐chloro‐N6 ‐cyclopentyladenosine (CCPA) in 8‐day‐old cultured neurons from fetal rat forebrain grown in serum‐free medium. [3H]CCPA bound specifically and with high affinity (Kd = 2.9 nM) to a homogeneous population of sites. Displacement of CCPA binding by various adenosine derivatives indicated that A1 receptors were selectively labeled. The presence of Gpp(NH)p, a GTP analogue, reduced significantly the binding affinity (Kd = 12.2 nM), suggesting that A1 receptors detected in intact cultured cells are linked to associated G proteins. © 1993 Wiley‐Liss, Inc.
Depolarization inactivation of dopamine neurons: Terminal release characteristics
Authors: Moghaddam Bita , Bunney Benjamin S.
Published: December 2004

The functional consequences of chronic treatment with haloperidol (0.5 mg/kg s. c. for 21–23 days) on striatal extracellular levels of dopamine and excitatory amino acids, aspartate and glutamate, were examined using microdialysis techniques. Our studies indicate that, in both awake and anesthetized animals, chronic haloperidol treatment does not appear to change basal outflow of dopamine and its response to an exogenous antagonist (i. e., a challenge dose of haloperidol). Furthermore, in chronic haloperidol and vehicle‐treated animals, extracellular dopamine levels were decreased below our limit of detection following perfusion of tetrodotoxin through the probe, or into the medial forebrain bundle, suggesting that in both groups of animals extracellular dopamine levels are neuronally derived and seemed to depend equally on impulse flow. However, some differences were observed between the vehicle and haloperidol‐treated animals: the excitatory action of 30 mM K+ on extracellular dopamine levels was decreased, and extracellular levels of glutamate were significantly increased, in animals treated chronically with haloperidol. The alterations in extracellular glutamate levels suggests that events at the terminal may be involved in maintaining the “normal” extracellular dopamine levels. Furthermore, the decrease in response to stimulation by K+ suggests that chronic haloperidol treatment may decrease the responsivity of the striatal dopamine system to stimuli. © 1993 Wiley‐Liss, Inc.
Paroxysmal long‐lasting depolarizations in cultured hippocampal neurons are generated by activation of NMDA and non‐NMDA receptors
Authors: Köller Hubertaus , Siebler Mario , Müller Hans Werner
Published: December 2004

In primary cultures of hippocampal neurons from the embryonic rat, spontaneous depolarizations lasting up to 6 sec adn resembling paroxysmal depolarization shifts (PDAs) appeared after 11 day7s in vitro. These depolarizations are presumably generated by sy6naptic events, because: (1) both their appearance and duration are independent of membrane potential, (2) the amplitudes of the underlying currents depend monotonically on membrane potential, and (1) they are reversed at the reversal potential of the excitatory postsynaptic potentials (EPSPs). In addition, PDAs disappeared reversiblyy when sodium‐dependent action potentials were blocked by tetrodotoxin (10μM) and when synaptic transmission was reduced by elevated Mg2+ (5mM). Further, the fact that these depolarizations can apppear simultaneously in two neurons in paired recordings also points to a synaptic origin. Inhibition of glutaminergic synaptic transmission by kynurenic acid (50μM) and the NMDA‐antagonist D‐2‐amino‐5‐phosphonovaleric acid (APV; 50μM) led to a marked shortening of the depolarizations. This blocking effect of kynurenic acid and APV and comparison with the currents elicited by locally applied glutamate or NMDA provide evidence for an activation of both types of glutamate receptors to induce PDSs. The role of alteration of glutaminergic synaptic transmission in the induction and maintenance of these depolarizations is discussed in the context of results from the literature on the appearrance of PDSs in cultures grown under chronic blockade of glutamate receptors. © 1993 Wiley‐Liss, Inc.
Spinal cord transection produces a long‐term increase in GABAB binding in the rat substantia gelatinosa
Authors: Kroin Jeffrey S. , Bianchi Gregory D. , Penn Richard D.
Published: December 2004

Quantitative autoradiography was used to determine changes in GABAB receptor binding in the substantia gelatinosa of the lumbar spinal cord at 4 days and at 6 weeks after a midthoracic spinal transection in rats.

In the 4 day lesion animals, there was no significant change in either the density or the affinity of the GABAB binding. At 6 weeks, however, there was a 35% increase in binding density, with no significant change in affinity. The results suggest that alterations in spinal synaptic mechanisms can slowly evolve following loss of descending input to the spinal cord. © 1993 Wiley‐Liss, Inc.
Autoradiographic localization of [125I‐TYR8]‐bradykinin receptor binding sites in the guinea pig spinal cord
Authors: Lopes Paulo , Kar Satyabrata , Tousignant Christine , Regoli Domenico , Quirion Réami , Couture Réjean
Published: December 2004

The present study aimed to localize and characterize [125I‐Tyr8]‐BK binding sites in all major segments of the guinea pig spinal cord using in vitro quantitative receptor autoradiography. [125I‐Tyr8]‐BK specific binding sites were localized predominantly in superficial layers of the dorsal horn, with lamina II depicting the highest labelling. The density of specific binding in laminae I and III was moderate, whereas in other areas, i.e., laminae IV‐X, lower amounts of labelling were noticed. The B2 receptor antagonists D‐Arg[Hyp3,Thi5,D‐Tic7,Oic8]‐BK (Hoe 140),D‐Arg[Hyp3,D‐Phe7,Leu8]‐BK,Tyr0,D‐Arg[Hyp3,D‐Phe7,Leu8]‐BK, D‐Arg[Tyr3,D‐Phe7,Leu8]‐BK, D‐Arg[Hyp2,Thi5.8,DPhe7]‐BK, D‐Arg[Hyp3,Leu8]‐BK and D‐Arg[Hyp3,Gly6,Leu8]‐BK as well a., unlabelled [Tyr8]‐BK inhibited [1251‐Tyr8]‐BK binding with respective Ki values of 0.04, 12.4, 23.4, 34.5, 43.5, 33.5, 23.0, and 0.6 nM while B1 related molecules (Tyr0, des‐Arg10‐kallidin and [Leu8]‐des‐Arg9‐BK) did not significantly inhibit [125I‐Tyr8]‐BK binding up to micromolar concentrations. These results indicate that the specific [125I‐Tyr8]‐BK binding sites present in the guinea pig spinal cord belong to the B2 receptor subtype. The high density of B2 binding sites in the substantia gelatinosa provides an anatomical evidence in favour of a role for BK as a modulator of nociceptive information. © 1993 Wiley‐Liss, Inc.
Evaluation of 5‐[18F]Fluoropropylepidepride as a potential pet radioligand for imaging dopamine D2 receptors
Authors: Kessler Robert M. , Votaw John R. , de Paulis Tomas , Bingham Daniel R. , Ansari M. Sib , Mason N. Scott , Holburn George , Schmidt Dennis E. , Votaw Delicia B. , Manning Ronald G. , Ebert Michael H.
Published: December 2004

This study evaluated the utility of (S)‐N‐[(1‐ethyl‐2‐pyrrolidinyl)methyl]‐5‐(3‐[18F]fluoropropyl)‐2,3‐dimethoxybenzamide ([18F]fluoropropylepidepride), [18F]5‐FPrEpid, as a ligar d for PET studies of cerebral dopamine D2 receptors. The in vitro affinity for the rat striatal dopamine D2 receptor, KD 138 pM, was determined by Scatchard analysis of in vitro binding to rat striatal homogenate. The apparent lipophilicity, log kw 1.6, was measured with reverse phase HPLC at pH 7.5. The receptor specificity was determined by competitive displacement of [18F]5‐FPrEpid by a variety of neurotransmitter ligands. Only dopamine D2 ligands displaced [18F]5‐FPrEpid with high affinity. Positron tomographic imaging studies in primates of [18F]5‐FPrEpid demonstrated a stable striatal uptake. of 0.02% injected dose/ml for up to 5 h after injection. The striatal: cerebellar ratio increased from 2 at 15 min, to 7 at 200 min, and to 10 at 300 min. Striatal uptake was displaceable by haloperidol (1 mg/kg) or raclopride (2.5 mg/kg) to cerebellar levels with a t1/2 of washout of 9 or 15 min. Striatal uptake was mildly susceptible to displacement by d‐amphetamine (1–2 mg/kg) released endogenous dopamine; d‐amphetamine administration produced a 10%/h increase in the rate of striatal washout. Although uptake in the striatum is reversible, an equilibrium between receptor bound [18F]5‐FPrEpid in striatum and [18F]5‐FPrEpid in plasma is not reached within 5 h postinjection. © 1993 Wiley‐Liss. Inc.
Specific neurophysiological effects of systemic nicotine on neurons in the nucleus accumbens
Authors: Hakan R. L. , Hart C. , Eyl C.
Published: December 2004

Extracellular recordings of single neurons within the nucleus accumbens (NAS) of halothane‐anesthetized rats have revealed that systemic nicotine injections (0.5 and 1.0 mg/kg, s.c.) inhibit the action potentials of normally inactive NAS neurons, evoked by fimbria stimulation (fimbria‐driven responses, n = 18). These nicotine inhibitions of fimbria‐driven NAS action potentials appear to be centrally mediated because they were reversed by subsequent systemic injections of the centrally acting nicotinic acetylcholine (nAch) antagonist, mecamylamine (1.0 mg/kg, s.c., n = 6), but not by the peripherally acting nAch antagonist, hexamethonium (2.0 mg/kg, s.c., n = 6). Fimbria‐driven NAS neurons were also tested with morphine (2.5 mg/kg, s.c.) in some experiments. Consistent with many past observations (Hakan et al., 1989), morphine did not affect these driven neurons. In other experiments, nicotine‐induced inhibition of NAS fimbria‐driven units was followed by haloperidol (0.5 mg/kg, s.c.), in attempts to reveal the possible role of dopamine in these effects. Haloperidol was successful at reversing nicotine inhibitions in only some cases (n = 2/6). Thus, the role of dopamine in these NAS responses to nicotine remains unclear. In contrast to the fimbria‐driven NAS responses, spontaneously active NAS neurons were not affected by nicotine injections yet were subsequently inhibited with systemic morphine. These results suggest a specific neuro‐pharmacological organization in the region of the nucleus accumbens that may relate to the qualitative and subjective differences in the experiential effects of different psychoactive drugs. Iontophoretic studies designed to localize further the site of these nicotine effects on NAS neurons are in progress. © 1993 Wiley‐Liss, Inc.
MK‐801 prevents the development of behavioral sensitization during repeated morphine administration
Authors: Jeziorski Michael , White Francis J. , Wolf Marina E.
Published: December 2004

Acute administration of morphine (10 mg/kg) to rats elicited an increase in locomotion that became sensitized upon repeated treatment over 14 days. Administration of the noncompetitive N‐methyl‐D‐aspartate receptor (NMDA) antagonist MK‐801 (0.1 or 0.25 mg/kg) prior to each morphine injection prevented the development of behavioral sensitization to morphine, an effect that persisted even after a 7‐day withdrawal from repeated treatment. Sensitization was also prevented by coadministration of the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg). In contrast, acute pretreatment with MK‐801 did not alter the response of sensitized rats to morphine challenge, indicating that MK‐801 does not prevent the expression of sensitization. When administered alone, MK‐801 produced stereotyped movements at moderate doses (0.25 rng/kg) and horizontal locomotion at higher‐ doses, (0.5 mg/kg). Repeated administration of 0.25 mg/kg MK‐801 elicited sensitization to its own locomotor stimulatory effects, such that this dose became capable of eliciting horizontal locomotion. Sensitization was not seen during repeated administration of 0.1 mg/kg MK‐801 or 10 mg/kg CGS 19755, although both of these pretreatments did produce a sensitized response to subsequent challenge with 0.25 mg/kg MK‐801. This effect was enhanced by coadministration of morphine, even though repeated administration of morphine alone failed to sensitize rats to MK‐801 challenge. These results suggest a complex interplay between NMDA and opioid receptors, such that NMDA antagonists prevent morphine sensitization while morphine enhances the ability of NMDA antagonists to elicit sensitization to their own locomotor stimulatory effects. © 1994 Wiley‐Liss, Inc.
Imaging endogenous dopamine competition with [11C]raclopride in the human brain
Authors: Volkow Nora D. , Wang Gene‐Jack , Fowler Joanna S. , Logan Jean , Schlyer David , Hitzemann Robert , Lieberman Jeffrey , Angrist Burton , Pappas Naomi , MacGregor Robert , Burr Gail , Cooper Thomas , Wolf Alfred P.
Published: December 2004

This study images dopamine release in response to a neurochemically specific challenge with the psychostimulant drug methylphenidate. Changes in synaptic dopamine induced by methylphenidate were evaluated with positron emission tomography and [11C]raclopride, a D2 receptor radioligand that is sensitive to endogenous dopamine. Methylphenidate significantly decreased striatal [11C]raclopride binding. The decrease was variable and was negatively correlated with age. Mood and anxiety at baseline, were also correlated with methylphenidate‐induced DA changes. This strategy provides a tool to investigate the responsiveness of the dopamine system in the normal and diseased human brain and to investigate the neurochemical correlates of behavior. © 1994 Wiley‐Liss, Inc.
Loss of paired‐pulse facilitation at the corticostriatal synapse of the aged rat
Authors: Walsh John P. , Ou Xiaorong
Published: December 2004

Changes in calcium (Ca2+) homeostasis have been proposed to contribute to the aging process. Paired‐pulse facilitation, a form of synaptic enhancement that relies upon an accumulation of Ca2+ in the presynaptic terminal, was used to examine the effect of aging at the corticostriatal synapse. Intracellular recordings in striatal neurons from young rats demonstrated a consistent enhancement in the second of two synaptic responses evoked by stimulation of the corpus callosum. In contrast, neurons from aged rats showed a consistent depression of the second synaptic response at identical pairing intervals. These differences were not explained by an age‐dependent increase in synaptic depression and demonstrate an alteration in the Ca2+‐mediated process of presynaptic facilitation. © 1994 Wiley‐Liss, Inc.
Analysis of synaptic inputs and targets of physiologically characterized neurons in rat frontal cortex: Combined in vivo intracellular recording and immunolabeling
Authors: Cowan Ronald L. , Sesack Susan R. , Van Bockstaele Elisabeth J. , Branchereau Pascal , Chan June , Pickel Virginia M.
Published: December 2004

Ultrastructural immunocytochemical identification of transmitters in afferent terminals and targets of individual physiologically characterized neurons is essential for understanding the complex circuitry within the mammalian neocortex. For this type of analysis, we examined the utility of combining in vivo intracellular recording and biocytin injections with silver intensified 1 nm immunogold labeling of GABA and the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH). These transmitters are found in local neurons and afferents known to prominently modulate the activity of pyramidal neurons in the neocortex. Individual neurons were physiologically characterlzea and filled with biocytin in the frontal cortex of anesthetized rats. The brains were then preserved by vascular perfusion with aldehydes. Single vibratome sections through the recording site were reacted (1) for immunoperoxidase detection of biocytin and (2) for immunogold labeling of GABA or TH. Dually labeled sections were processed for light microscopy or embedded in plastic for electron microscopy. The dense peroxidase product for biocytin was detected in pyramidal neurons. These were located in superficial as well as deep cortical laminae. and were readily distinguished from immunogold silver labeling. GABA labeled terminals formed symmetric synapses with larger biocytin filled dendrites, whereas the TH labeled terminals contacted distal dendrites and spines. Peroxidase labeling for biocytin also was seen in a few axon terminals forming synapses with unlabeled and with GABA immunoreactive dendrites. These results suggest that single pyramidal neurons of the rat frontal cortex receive dual input from both GABA and catecholamine terminals. Additionally, this study demonstrates the usefulness of silver enhancement of 1 nm coilloidal gold prior to plastic embedding for electron microscopic detection of neurotransmitters within afferents and targets of neurons physiologically characterized in vivo. © 1994 Wiley‐Liss. Inc.
Dopamine D2 receptors mapped in rat brain with [3H](+)PHNO
Authors: Nobrega Jose N. , Seeman Philip
Published: December 2004

Previous work with membrane preparations had demonstrated that the agonist (+)‐4‐propyl‐9‐hydroxynaphthoxazine (PHNO) labels the high‐affinity state of dopamine D2 receptors with 67‐fold selectivity over D1 sites. In this study, quantitative autoradiography was used to examine the binding of [3H](+)PHNO to rat brain sections. Highest binding densities were found in caudate‐putamen, accumbens, and olfactory tubercles, as expected, and also in specific layers of the olfactory bulb. In addition, a second group of brain regions, including lateral septum, entorhinal cortex, molecular layer of hippocampus, and several brainstem structures showed low but consistent levels of binding. In all brain regions [3H](+)PHNO binding (2 nM) was completely displaced by 10 μM sulpiride (>99%). Addition of 150 μM guanilylimidodiphosphate, which normally converts D2 receptors from high to low affinity states, abolished [3H](+)PHNO binding in all brain regions (>99%), except for the islands of Callejas. This is likely to reflect binding to D3 sites in this area. Omission of preincubation in binding assays decreased [3H](+)PHNO binding in a regionally dependent manner, with strongest effects (22%) seen in high‐density areas. These preincubation results confirm that (+)PHNO may have limitations for in vivo imaging studies. On the other hand, [3H](+)PHNOs negligible levels of non‐specific binding compared to other agonists and overall selectivity would make it an excellent tool for in vitro autoradiographic monitoring of the high affinity state of D2 receptors. © 1994 Wiley‐Liss. Inc.
Sigma‐1 and Sigma‐2 sites in rat brain: Comparison of regional, ontogenetic, and subcellular patterns
Authors: McCann David J. , Weissman Arthur D. , Su Tsung‐Ping
Published: December 2004

Radioligand binding assay conditions were established for the selective labeling of sigma‐1 and sigma‐2 sites in membrane homogenates of rat brain. Selective sigma‐1 assays were conducted using 5 nM (+)[3H]SKF‐10,047 in the presence of 300 nM dizocilpine (MK‐801). Selective sigma‐2 assays were conducted using 5 nM [3H]DTG in the presence of 1 μM (+)SKF‐10,047. Distributions of sigma‐1 and sigma‐2 binding among brain regions were found to differ. While the brain stem yields the highest level of sigma‐1 binding, it yields among the lowest levels of sigma‐2 binding. The reverse is true in hippocampal membranes. Different ontogenetic patterns were also observed. Sigma‐2 binding decreases substantially during brain development, whereas sigma‐1 binding does not vary significantly. Patterns of distribution among subcellular fractions of rat brain homogenates were found to be similar. Both sigma‐1 and sigma‐2 sites are most enriched in microsomal fractions, and neither is enriched in synaptosomal or mitochondrial fractions. The present results suggest that sigma‐1 and sigma‐2 sites are distinct entities; they do not appear to be located on a common macromolecule, and they do not represent two different affinity states of a single type of binding site. While the precise subcellular locations (if sigma‐1 and sigma‐2) sites remain to be determined, we conclude that localization of either type of binding site to synaptic regions of plasma membrane or to mitochondria is highly unlikely © 1994 Wiley‐Liss, Inc.

This article is a US Government work and, as such is in the public domain in the United States of America.
Dopamine displays an identical apparent affinity towards functional dopamine D1 and D2 receptors in rat striatal slices: Possible implications for the regulatory role of D2 receptors
Authors: Schoffelmeer Anton N. M. , Hogenboom Francois , Mulder Arie H. , Ronken Eric , Stoof Johannes C. , Drukarch Benjamin
Published: December 2004

In this study we examined the selectivity of dopamine (DA) for rat striatal DA D1 and D2 receptors. In a Krebs‐HEPES buffer, the Ki values of DA for D1 binding sites (labelled with [3H]SCH23390) and D2 binding sites (labelled with [3H]spiroperidol) in striatal membranes amounted to about 30 and.0.3 μM, respectively. However, the EC50s of DA (3 μM) and the DA releasing drug amphetamine (1 μM) were identical considering D1 receptor‐stimulated and D2 receptor‐inhibited adenylate cyclase activity in superfused striatal slices. Moreover, these EC50 values were also obtained studying DA‐ and amphetamine‐induced D2 receptor activation, resulting in inhibition of the electrically evoked release of [14C]acetylcholine from the slices. Therefore, with regard to the apparent affinity of exogenous and endogenous DA for D1 and D2 receptors in rat striatal slices, the ligand‐receptor binding data appeared to be misleading. Thus, our data show that in rat striatal slices DA has an identical apparent affinity towards functional D1 and D2 receptors, which is particularly intriguing in view of the very high receptor selectivity of synthetic D1 and D2 receptor agonists for these functional receptors in superfused brain slices as predicted on the basis of binding assays. This may have important implications for our understanding of central DA neurotransmission. For instance, since the inhibitory effect of opioid and muscarinic receptor activation on adenylate cyclase activity has been shown to be inversely related to the degree of DA D2 receptor activation, the degree of activation of D1 and D2 receptors by released DA is suggested to act as a functional gate allowing distinct neurotransmitters to play a role in striatal neurotransmission. © 1994 Wiley‐Liss, Inc.
Effects of prenatal cocaine exposure upon postnatal development of neostriatal dopaminergic function
Authors: Leslie Catherine A. , Robertson Matthew W. , Jung Anthony B. , Liebermann Jennifer , Bennett James P.
Published: December 2004

Pregnant rats were injected twice daily with 20 mg/kg cocaine (or saline) from gestational day 10 to parturition. Brains from offspring were examined with quantitative receptor autoradiography [D1 receptor (D1R), D2 receptor (D2R) and dopamine transporter (DAT)] and quantitative in situ hybridization [D1R mRNA, D2R mRNA, preproenkephalin (PPE) mRNA] for markers of neostriatal dopaminergic function. Prenatal cocaine exposure did not alter postnatal development of striatal D1R sites, but D1R mRNA levels were reduced by a third at days 14 and 35. D2R sites were increased over control in lateral striatum by day 6, and remained elevated through postnatal day 35. Total D2R mRNA was increased over control in both medial and lateral striatum at 7 and 14 days but was equal to control at 35 days. Prenatal cocaine exposure increased DAT density at postnatal days 1 through 5, but reduced it at days 14 and 35; PPE mRNA expression was reduced at days 7, 14 and 35. Many of these results are similar to those found in experimental animals and humans following cocaine withdrawal. © 1994 Wiley‐Liss, Inc.
GABA‐Ergic interneurons of the striatum express the shaw‐like potassium channel KvS3.1
Authors: Lenz S. , Perney T. M. , Qin Y. , Robbins E. , Chesselet M.‐F.
Published: December 2004

In addition to numerous GABA‐ergic efferent neurons, the striatum contains a subpopulation of fast‐firing GABA‐ergic interneurons characterized by the presence of immunoreactivity for the calcium‐binding protein, parvalbumin. Doublelabel in situ hybridization with digoxigenin‐ and radiolabelled cRNA probes was performed on striatal: sections of adult rats to identify mRNAs expressed by striatal GABAergic interneurons. In the dorsolateral striatum, only parvalbumin mRNA‐positive neurons expressed the mRNA encoding the potassium channel Kv3.1, a member of the Shaw family of potassium channels with rapid activation and inactivation kinetics, usually found in fast‐firing neurons such as the basket cells of the hippocampus. Colocalization of the parvalbumin and Kv3.1 proteins was confirmed by double‐label immunohistochemistry. Parvalbumin mRNA‐positive neurons expressed very high levels of the mRNA encoding glutamic acid decarboxylase (Mr 67,000: GAD67) in the dorsolateral striatum. A smaller proportion of double‐labelled neurons was found in the ventrolateral striatum. A small number of densely labelled neurons for GAD67 mRNA also expressed the mRNA encoding the dopamine D2 receptor, but none expressed detectable levels of the dopamine D1 receptor mRNA. This indicates major differences in the expression of dopamine receptor mRNA in a majority of GABA‐ergic interneurons vs. GABA‐ergic efferent neurons of the striatum. The results suggest that distinct molecular characteristics are associated with the distinct electrophysiological properties of striatal GABA‐ergic neurons. © 1994 Wi1ey‐Liss; Inc.
Modulation of dorsal thalamic cell activity by the ventral pallidum: Its role in the regulation of thalamocortical activity by the basal ganglia
Authors: Lavín Antonieta , Grace Anthony A.
Published: December 2004

The actions mediated by limbic system output projections of the basal ganglia were investigated by studying the effects of ventral pallidum (VP) stimulation on the activity of neurons in thalamic target nuclei, including several of the dorsal thalamic nuclei and the nucleus reticularis, using in vivo intracellular recordings in rats. Intracellular injection of Lucifer yellow was used in a subset of experiments to identify the neurons recorded and to confirm their location with respect to the specific thalamic nuclei targeted. Stimulation of the VP evoked ipsps in 79% of the mediodorsal cells recorded. In the reticular nucleus, 73% of the neurons tested responded with evoked ipsps. In contrast, in other dorsal thalamic nuclei VP stimulation evoked depolarizations in 58% of the cells recorded. The latency to onset of the ipsps in the mediodorsal nucleus and in the reticular nucleus were not substantially different (1.7 ± 1.1 msec vs. 2.7 ± 1.1 msec), whereas the depolarizing response evoked in dorsal thalamic nucleus neurons typically occurred at longer and more variable latencies (3.5 ± 2.7 msec).
Alterations in mRNA levels of D2 receptors and neuropeptides in striatonigral and striatopallidal neurons of rats with neuroleptic‐induced dyskinesias
Authors: Egan Michael F. , Hurd Yasmin , Hyde Thomas M. , Weinberger Daniel R. , Wyatt Richard Jed , Kleinman Joel E.
Published: December 2004

Chronic neuroleptic treatment in rat produces vacuous chewing movements (VCMs), analogous to TD in humans. We hypothesized that these hyperkinetic movements were due to alterations in striatonigral and striatopallidal GABAergic spiny II neurons. Rats were treated for 36 weeks with haloperidol decanoate and withdrawn for 28 weeks. Striatonigral and striatopallidal neurons were assessed using in situ hybridization histochemistry for mRNA levels of D1 and D2 dopamine receptors, preproenkephalin (ENK), prodynorphin (DYN), protachykinin (substance P), and glutamate decarboxylase (GAD67) in the dorsolateral and ventromedial striatum as well as the nucleus accumbens. Rats that did not develop VCMs (‐ VCM) had increased D2 receptor and DYN mRNA, and reduced substance P mRNA in the dorsolateral striatum. Rats with persistent VCMs (+VCM,) had increased D2 receptor, ENK, and DYN mRNA in both striatal regions, and increased ENK and DYN mRNA in the nucleus accumbens, compared with controls. Relative to ‐VCM rats, however, +VCM rats only had increased ENK mRNA in the nucleus accumbens. Considering the overall pattern of mRNA changes, the data suggest that alterations in both the D1‐mediated striatonigral and the D2‐mediated striatopallidal pathways play a role in the expression of the VCM syndrome. To the extent that gene expression parallels changes in neuronal activity, this implies that the VCM syndrome is associated with increased activity in both pathways. © 1994 Wiley‐Liss, Inc

This article is a US Government work and as such, is in the public domain in the United States of America.
Three‐dimensional quantification of mossy‐fiber. Presynaptic boutons in living hippocampal slices using confocal microscopy
Authors: Yu Tzu‐Ping , Brown Thomas H.
Published: December 2004

Confocal laser scanning microscopy (CLSM) was used to visualize presynaptic elements of mossy‐fiber synapses in living rat hippocampal slices. Mossy fiber (mf) axons and their boutons were labeled in transverse hippocampal slices by injecting one of three fluorescent dyes (diI, diA, or fast diI) into stratum granulosum of the dentate gyrus and/or stratum lucidum of CA3. Three‐dimensional (3D) images of the mf boutons were obtained from serial optical sections in stratum lucidum. The 3D data were used to quantify and characterize the size and shape of the boutons based on their volumes (V) and surface areas (A), and the latter were compared with conventional 2D analyses. Various geometric models were fitted to the V‐A relationship, one of which provided a reasonable approximation to the data. The results demonstrate that this approach is useful for quantifying and characterizing the size and shape of mf expansions and raise the possibility of detecting and analyzing in real time activity‐dependent modifications in presynaptic structure. © 1994 Wiley‐Liss, Inc.