bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic ethanol exposure enhances [3H]GABA release and does not affect GABAA receptor mediated 36Cl uptake
Authors: Tremwel Margaret F. , Hunter Bruce E. , Peris Joanna
Published: December 2004

Chronic ethanol treatment (CET) produces a permanent reduction in hippocampal long‐term potentiation (LTP). The CET produced reduction of LTP can be eliminated acutely by Pharmacological blockade of γ‐aminobutyric acid (GABA)ergicA synaptic transmission with the specific antagonist, bicuculline methiodide. Since LTP induction is normally modulated by activation of GABAergic synaptic transmission, we hypothesized that CET reduced LTP by enhancing either postsynaptic GABAA channel function or GABA release from presynaptic terminals. In the present study, we examined the long term effects of CET on GABAA channel function by measuring the efficacy of GABA to stimulate and bicuculline to antagonize GABA‐stimulated 36Cl− uptake in hippocampal and cortical membrane preparations. CET did not affect basal uptake of chloride or the efficacy or either GABA or bicuculline at the GABAA channel. We next measured the long term effects of CET on basal and stimulated GABA release. When basal and electrically‐stimulated [3H]GABA release were measured in superfused hippocampal slices, stimulated release was increased by 30% in CET rats. Basal release was unaffected. Thus it appears that CET may be reducing LTP by enhancing plasticityrelated GABA release from presynaptic terminals. © 1994 Wiley‐Lisa, Inc.
Electrophysiological evidence for a functional interaction between 5‐HT1A and 5‐HT2A receptors in the rat medial prefrontal cortex: An lontophoretic study
Authors: Ashby Charles R. , Edwards Emmeline , Wang Rex Y.
Published: December 2004

In this study, we examined the interaction of 5‐HT1A and 5‐HT2A receptors in the rat medial prefrontal cortex (mPFc) using the techniques of extracellular single unit recording and microiontophoresis. The iontophoresis of the selective 5‐HT1A receptor agonist (±)‐8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OHDPAT) produced a current‐dependent suppression (2.5‐20 nA) of the basal firing rate of spontaneously active mPFc cells. The iontophoretic (5‐10 nA) and systemic administration (0.1‐0.5 mg/kg, i.v. ) of the 5‐HT2A/5‐HT2C receptor antagonist ritanserin and the selective 5 HT2A receptor antagonist MDL 28727 significantly potentiated and prolonged 8‐OHDPATs suppressant action. In addition, the systemic administration of another selective 5‐HT2A antagonist MDL 100907, but not its less active enantiomer MDL 100009, also potentiated and prolonged 8‐OHDPATs action. The potentiating effect of the 5‐HT2A receptor antagonists on the action of 8‐OHDPAT is specific in that neither the iontophoresis of ritanserin nor MDL 28727 altered the suppressant action produced by the iontophoresis of the 5‐HT3 receptor agonist 2‐methylserotonin onto mPFc cells. Moreover, the suppressant action of 8‐OHDPAT was not altered by the systemic administration of the selective 5‐HT3 receptor antagonist granisetron (0.1‐0.5 mg/kg, i.v.). On the other hand, the iontophoresis of a low current (0.5 nA) of the 5‐HT2A,2C receptor agonist (±)‐1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI) potentiated the excitation induced by the iontophoresis of 1‐glutamate on quiescent mPFc cells. The iontophoresis of 8‐OHD‐PAT at a current that had no effect on the firing rate of 1‐glutamate activated when administered alone significantly attenuated the excitatory action produced by the iontophoresis of DOI. Overall these results confirm and extend the hypothesis that there is an interaction between 5‐HT1A and 5‐HT2A receptors in the mPFc at the neuronal level. © 1994 Wiley‐Liss, Inc.
Insulin‐like growth factor‐I receptors in human brain and pituitary gland: An autoradiographic study
Authors: De Keyser Jacques , Wilczak Nadine , De Backer Jean‐Paul , Herroelen Luc , Vauquelin G.
Published: December 2004

Insulin‐like growth factor (IGF)‐I receptors were studied in adult human postmortem brain and pituitary gland using quantitative autoradiography with human recombinant [125I]IGF‐I. The highest densities were found in the choroid plexus, pituitary gland‐where IGF‐I receptors were mainly concentrated in the anterior lobe, pineal gland, glomerular layer of the olfactory bulb, and the molecular layer of the cerebellar cortex. Moderate densities were present in cerebral cortex, caudate nucleus, putamen, accumbens, the CA1, CA2, CA3 fields and dentate gyrus of the hippocampus, the dendate nucleus of the cerebellum, amygdala, thalamus, pontine nuclei, and substantia nigra. All other brain areas, including white matter, contained low densities of IGF‐I receptors. The finding that several well‐defined brain structures are enriched with IGF‐I receptors suggests a rieurotrophic/survival or neuromodulatory role of insulin‐like growth factors on specific neuronal systems. IGF‐I receptors observed in the white matter may be associated with oligodendrocytes. © 1994 Wiley‐Liss, Inc.
Methamphetamine‐induced neurotoxicity: Roles for glutamate and dopamine efflux
Authors: Stephans Stacy E. , Yamamoto Bryan K.
Published: December 2004

The neurotoxic effect of methamphetamine (METH) on striatal dopaminergic neurons have been hypothesized to be mediated by excess dopamine (DA) release. In addition, N‐methyl‐D‐aspartate (NMDA) receptor antagonists block METH‐induced DA depletions. This suggests that glutamate also mediates the toxic effects of METH. The purpose of this study is to demonstrate that DA and glutamate efflux contribute to METH‐inducted neurotoxicity.

In vivo microdialysis in rats was used to measure extracellular concentrations of striatal DA and glutamate following 3 injections of METH (10 mg/kg, i.p.), each injection given 2 hours apart. One week following the dialysis experiment, rats were sacrificed and the ventral lateral striata were assayed for DA content. Glutamate concentrations in the dialysate increased by over 4‐fold after the third METH injection. In these same animals, striatal DA tissue content was significantly depleted. In separate groups of rats, pretreatment with haloperidol (2 mg/kg at the first METH injection) significantly increased METH‐induced DA efflux. The haloperidel pretreatment attenuated the extracellular increase in glutamate produced by METH and blocked subsequent neurotoxicity to DA neurons. In contrast, pretreatment with the DA uptake blocker, GBR‐12909 (10 mg/kg, 30 min before each METH injection) significantly attenuated the increased DA release produced by METH but did not change glutamate efflux. However, pretreatment with GBR‐12909 did protect against the tissue content depletion of DA in the striatum. Based on these findings, it appears that increased DA and glutamate release in the striatum are important and possibly interact in the development of METH‐induced neurotoxicity. © 1994 Wiley‐Liss, Inc.
Pharmacologically induced cessation of burst activity in nigral dopamine neurons: Significance for the terminal dopamine efflux
Authors: Nissbrandt Hans , Elverfors Anders , Engberg Goran
Published: December 2004

Results obtained previously indicate that the firing pattern of midbrain dopamine (DA) neurons is of importance for the terminal DA release. In the present combined electrophysiological and microdialysis study, the influence of the firing pattern on striatal DA release was studied by using the previously observed ability of low doses of β‐hydroxybutyrate (GHBA) to profoundly regularise the firing pattern of rat DA neurons in the substantia nigra (SN). Administration of GHBA (200 mg/kg, i.v.) did not significantly reduce the firing rate of any of the DA neurons recorded from, but rather caused a slight transient excitation. However, this dose of the drug caused a profound regularisation of the firing pattern and abolished burst activity of the DA neurons. The DA concentration in the dialysate obtained from the striatum (10 min sampling periods) decreased with the lowest value (67% of predrug value) observed at the sampling period 20‐30 min after the GHBA administration. As a complement to microdialysis, the 3‐methoxytyramine (3‐MT) accumulation in striatal tissue following monoamine oxidase inhibition was determined as an indirect measure of DA release in vivo. The 3‐MT concentrations in the striatum decreased to 84% of controls following 200 mg/kg of GHBA. To exclude an effect on DA release conceivably mediated by GHBA locally in the striatum, GHBA (10−7‐10−3 M) was given locally in the dialysis probe and was found to increase DA in the dialysate (maximally to 140% of controls). The present results are in line with previous electrophysiological studies which have demonstrated that artificially induced burst firing by electrical stimulation is associated with an increased extracellular level of striatal DA (as determined by in vivo voltammetric techniques or microdialysis) and support the idea that firing pattern may be an important physiological modulatory mechanism for the release of terminal neurotransmitter. © 1994 Wiley‐Liss, Inc.
Insulin‐like growth factor binding protein‐1 at mouse neuromuscular synapses
Authors: Ma Jianxin , Yang Shi , Ho Gilbert J. , Festoff Barry W.
Published: December 2004

The insulin‐like growth factor (IGF) signaling system includes the growth factors and their cell surface receptors, along with circulating IGF binding proteins (IGFBPs) that may alter and modulate the action of these neurotrophic hormones. These IGFBPs, along with IGFs and receptors, have been detected in various tissues including the brain. In this study, using polyclonal antibody to human IGFBP‐1 or bovine IGFBP‐2, we found that mouse muscle extracts contain similar‐sized proteins that crossreact with these antibodies on Western immunoblots. After establishing that these antibodies reacted with the homologous murine IGFBPs, we performed immunocytochemistry to demonstrate the localization of IGFBP‐1 at the neuromuscular junction, a model nicotinic, cholinergic synapse, as well as within intramuscular nerves. IGFBP‐2, a distinct macromolecule, is present on the surface of muscle fibers and is not present within synapses or nerves. © 1994 Wiley‐Liss, Inc.
Dopamine neuron membrane physiology: Characterization of the transient outward current (IA) and demonstration of a common signal transduction pathway for IA and IK
Authors: Liu Lixin , Shen Roh‐Yu , Kapatos Gregory , Chiodo Louis A.
Published: December 2004

Dopamine neurons derived from the mesencephalon of embryonic rats were maintained in primary culture, identified and studied with whole‐cell patch recording techniques. These neurons demonstrated a rapidly activating and inactivating voltage‐dependent outward current which required the presence of K+ ions. This current was termed IA because of its transient nature. It was elicited by step depolarizations from holding potentials more negative than ‐50 mV and exhibited steady‐state inactivation at a membrane potential more positive than ‐40 mV and half‐maximal inactivation observed at ‐65 mV. This current rapidly achieved peak activation in less than 8 msec and decayed with a time constant (τ) of 58±5 msec. This current was observed in the presence of tetraethylammonium but was readily blocked by 4‐aminopyridine (2‐4 mM). This current was also observed to be modulated by stimulation of D2 dopamine receptors (DA autoreceptors) located on the dopamine neurons. Thus, both DA and the D2 receptor agonist quinpirole enhanced the peak IA observed, while the partial D1 receptor agonist SKF 38393 was without effect. The enhancement of IA was confirmed to be due to the activation of D2 receptors as the effects of either DA or quinpirole were blocked by the D2 receptor antagonists eticlopride and sulpiride, but not by the D1 receptor antagonist SCH 23390. Since we have previously demonstrated that the IK present: in these cells is also enhanced by D2 receptor stimulation, we investigated the signal transduction pathways involved in coupling DA autoreceptors to both IA and IK. The response of both these potassium currents to DA autoreceptor stimulation was completely abolished by the preincubation of cultures with pertussis toxin, indicating the possible involvement of the G proteins Gi and GO. In an attempt to further characterize which G protein may be involved, additional experiments were performed. The ability of DA autoreceptor stimulation to augment both currents was also blocked completely when G protein activation was prevented by the intracellular application of GDPßS (100 μM). In contrast, irreversible activation of G proteins by intracellular application of the nonhydrolyzable GTP analog GTPγS (100 μM) mimicked the effects of DA autoreceptor stimulation on both IA and IK. In addition, the intracellular application of a polyclonal antibody that was selective for the β‐subunit of GO completely abolished the DA autoreceptor modulation of both currents while preimmune serum was without effect. Taken together, these data demonstrate that the enhancement of IA and IK in response to stimulation of DA autoreceptors is dependent upon the activation of GO and appears to involve a GOα subunit. © 1994 Wiley‐Liss, Inc.
Calcium signalling in bovine adrenal chromaffin cells: Additive effects of histamine and nicotine
Authors: Firestone Jordan A. , Browning Michael D.
Published: December 2004

In a previous report, we described the ability of two secretogogues, histamine and nicotine, to stimulate additive effects on catecholamine (CA) release and synapsin II phosphorylation in bovine adrenal chromaffin cells (BACC) [Firestone and Browning (1992), J. Neurochem., 58:441–447]. We hypothesized that these results were due to the combined effects on cytosolic Ca++ of the two distinct signalling pathways. We therefore examined the intracellular Ca++ signals stimulated by histamine and nicotine, alone and together. In Ca++ ‐deficient medium, nicotine‐stimulated signals were abolished, whereas histamine‐stimulated signals were maintained, demonstrating that nicotine depended entirely on Ca++ influx for its effects. Indeed, the nicotine‐stimulated signal could also be prevented using a Ca++ channel blocker, nicardipine. Further, the observation that exposure of BACC to thapsigargin reduced histamine‐stimulated Ca++ signals verified that histamine mobilizes Ca++ from intracellular stores. Thus, the two secretogogues mobilize Ca++ from distinct pools. When BACC were stimulated with the two secretogogues together, the resulting Ca++ signal was greater than that from either alone. These data are consistent with a model in which two distinct sources of Ca++ can summate within the cell, producing a greater Ca++ signal and, hence, a greater effect on neurotransmitter release. © 1994 Wiley‐Liss, Inc.
Age‐dependent appearance of synaptic currents in rat neocortical neurons in culture
Authors: Zona Cristina , Palma Eleonora , Brancati Aldo , Avoli Massimo
Published: December 2004

Rat neocortical neurons grown in dissociated cell culture were recorded with the whole‐cell patch‐clamp technique. Spontaneous inward currents were observed in cells that were held at a membrane potential of −80 mV in medium containing tetrodotoxin and Cd2+. These currents displayed amplitudes up to 140 pA and rise time of 1.8 ± 0.2 ms (mean ± SD, n = 15). They reversed near 0 mV and showed no voltage‐dependent frequency of occurrence. Hence, they were presumably due to spontaneous release of transmitter. The inward currents appeared around day 10 in culture and were detected up to 4 weeks. When cells of different ages were compared, the maximal probability of recording these inward events occurred at around 3 weeks in culture. The inward currents were not reduced by application of bicuculline methiodide which is a competitive antagonist of the GABAA receptor, but were blocked by the broad‐spectrum glutamate receptor antagonist kynurenic acid. Moreover, spontaneous inward events were not affected by DL‐2‐aminophosphono‐valerate (NMDA receptor antagonist) but disappeared following application of the non‐NMDA receptors antagonist 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX). Our observations indicate that the inward currents represent miniature synaptic events that are primarily mediated by non‐NMDA excitatory amino acid receptor subtypes. Furthermore, our findings indicate that they develop over time and are not present in neurons that are grown in culture for less than 10 days. © 1994 Wiley‐Liss, Inc.
Immunohistochemical evidence for GABA and glycine‐containing trigeminal premotoneurons in the guinea pig
Authors: Turman Jack , Chandler Scott H.
Published: December 2004

Electrophysiological studies have suggested that inhibition of trigeminal motoneurons during mastication and the jaw‐opening reflex are mediated by last‐order interneurons (premotoneurons) utilizing GABA and glycine [Chandler et al. (1985), Brain Res., 325:181–186; Enomoto et al. (1987), Neurosci. Res., 4:396–412; Goldberg and Nakamura (1968), Experientia, 24:371–373; Kidokoro et al. (1968), J. Neurophysiol., 31:695–708; Nakamura et al. (1978), Exp. Neurol., 61:1–14]. In the present study we performed a series of double‐labeling experiments in guinea pigs to determine the location of neurons which contain GABA (gamma aminobutyric acid) or glycine that project to the trigeminal motor nucleus (Mo5). This was accomplished by performing immunohistochemical staining in combination with a retrograde tract tracing technique using colloidal gold bound to inactivated WGA‐HRP (wheat germ agglutin‐horseradish peroxidase) (gWGA‐HRP) as our retrograde tracer. Neurons which had a positive immunoreactivity to GABA or GAD (glutamic acid decarboxylase) and contained the retrograde marker were located in regions adjacent to the Mo5 such as the intertrigeminal, supratrigeminal, peritrigeminal and rostral portions of the parvocellular reticular formation alpha. Neurons which had a positive immunoreactivity to glycine and contained the retrograde marker were identified in the parvocellular reticular formation, the spinal trigeminal nucleus oralis, supratrigeminal and intertrigeminal regions. These data provide anatomical evidence for GABAergic and glycinergic projections to Mo5. © 1994 Wiley‐Liss, Inc.
Ethanol differentially modulates GABAA receptor‐mediated chloride currents in hippocampal, cortical, and septal neurons in rat brain slices
Authors: Soldo Brandi L. , Proctor William R. , Dunwiddie Thomas V.
Published: December 2004

Previous electrophysiological studies have reported conflicting results concerning the effects of ethanol on γ‐aminobutyric acid‐A (GABAA) receptor‐mediated responses in the brain. To examine the variables that might explain these inconsistencies, the present study was designed to determine whether ethanol modulation of synaptically evoked GABA responses is brain region dependent, to identify factors that might regulate ethanol sensitivity, and to investigate the mechanism(s) underlying ethanol modulation of GABA responses. Whole‐cell voltage clamp methods were used to examine the effects of ethanol on synaptically evoked GABAA inhibitory postsynaptic currents (IPSCs) recorded from neurons in hippocampus, cerebral cortex, and intermediate lateral and medial septum from rat brain slice preparations. Bicuculline‐sensitive IPSCs elicited by local stimulation were pharmacologically isolated by pretreatment with the glutamate specific antagonists, DL‐(−)‐2‐amino‐5‐phosphonovaleric acid (APV) and 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX). Superfused ethanol (80 mM) potentiated evoked GABAA IPSCs in cortical neurons and in intermediate lateral and medial septal neurons but not in CA1 hippocampal neurons. However, the mechanism by which ethanol enhanced GABAA IPSC amplitudes differed between brain regions. In cortex, ethanol induced a hyperpolarizing shift in the GABAA IPSC reversal potential (EIPSC) without modifying the underlying GABAA receptor‐mediated conductance (GIPSC). In contrast, ethanol enhanced GABAA IPSC amplitudes in lateral and medial septal neurons by increasing the GIPSC without modifying the EIPSC These results suggest that ethanol differentially modulates responses to endogenous GABA released during synaptic activation and that important differences between various brain regions may reflect multiple mechanisms of ethanol action. © 1994 Wiley‐Liss, Inc.
Properties of inhibitory and excitatory synapses between hippocampal neurons in very low density cultures
Authors: Wilcox Karen S. , Buchhalter Jeffrey , Dichter Marc A.
Published: December 2004

The whole cell patch clamp technique was used to examine the electrophysiological properties of embryonic hippocampal neurons maintained in a very low density (VLD) culture prejparation. The goal of these experiments was to establish the viability of the VLD culture as a model system in which to study regulation of neurotransmission at single monosynaptic connections, in the absence of polysynaptic innervation. Depolarization of neurons in the VLD culture revealed voltage‐dependent sodium, calcium, and potassium currents which were blocked with, respectively, tetrodotoxin (TTX), cobalt, and tetraethylammonium and 4‐aminopyridine. When pairs of neurons were simultaneously recorded, action potentials evoked in presynaptic neurons elicited either excitatory or inhibitory postsynaptic currents (EPSCs or IPSCs, respectively). The dual component “EPSCs” were due to the activation of both types‐of postsynaptic, ionotropic glutamate receptors: N‐methyl‐D‐aspartate (NMDA) and non‐NMDA receptors. Evoked IPSCs were due to the activation of postsynaptic γ‐aminobutyric acid (GABA) receptors. Both excitatory and inhibitory synapses exhibited short term depression in response to high frequency stimulation, although IPSCs were routinely decreased to a much greater degree than EPSCs. Spontaneous miniature EPSCs and IPSCs were found to persist in TTX, were blocked by the same pharmacological antagonists which blocked evoked responses, increased in frequency in response to hyperosmotic solution, and were unaffected by changes in extracellular calcium concentration. mIPSCS were found to occur at a significantly lower frequency than mEPSCs. These experiments indicated that neurotransmission in the VLD cultures occurs in a manner consistent with the quantal hypothesis and, therefore, the VLD culture is a good model for studying excitatory and inhibitory neurotransmission between isolated pairs of neurons. In addition, these experiments, performed under comparable physiological conditions, demonstrated that there are fundamental differences underlying neurotransmitter release between excitatory and inhibitory neurons. © 1994 Wiley‐Liss, Inc.
Acute administration of alcohol blocks cocaine‐induced striatal c‐fos immunoreactivity protein in the rat
Authors: Torres German
Published: December 2004

Immediate‐early genes, such as c‐fos, are induced in the brain by cocaine and other psychotropic drugs. This induction is thought to be mediated via the activation of dopamine D1 and glutamate N‐methyl‐D‐aspartate (NMDA) receptor subtypes. Because alcohol selectively blocks NMDA receptor function, we determined the ability of alcohol to block the expression of c‐fos normally induced by systemic cocaine exposure in perikarya of the rat striatum. Acute administration of alcohol (2 g/kg; IP) approximately 30 min prior to a single cocaine (20 mg/kg) injection significantly reduced the patchy appearance of intensely immunoreactive gene signal in dorsal‐central quadrants of the caudate putamen. Separate administration of three doses of alcohol alone (1, 2, or 3 g/kg) was ineffectual in inducing FOS‐like protein in this or other regions of the rat brain. The blockade of the encoded protein by alcohol was partial in magnitude reminiscent of that produced by MK‐801 and related NMDA receptor antagonist drugs. Furthermore, the blockade of cocaine‐induced FOS‐like protein by alcohol occurred at a dose which produced a blood alcohol concentration of approximately 180 mg/dl (40 mM), comparable to that detected in intoxicating humans. Considering the fact that the concomitant use of alcohol and cocaine is the most common substance abuse pattern found in the addictive population, the present results suggest an antagonistic effect exerted by these two drugs at the transcriptional level and further support the consensus that NMDA receptors are the plausible surface‐target elements mediating some of the effects of alcohol and cocaine. © 1994 Wiley‐Liss, Inc.
Differences in the Cs block of baclofen and 4‐aminopyridine induced potassium currents of guinea pig CA3 neurons in vitro
Authors: Jarolimek Wolfgang , Bijak Maria , Misgeld Ulrich
Published: December 2004

Single‐electrode current‐ and voltage‐clamp techniques were employed to study responses elicited by (−)baclofen or γ‐aminobutyric acid (GABA) and 4‐aminopyridine (4‐AP) induced inhibitory postsynaptic potentials in CA3 pyramidal neurons in guinea pig hippocampal slices. All drugs were applied by the bath to submerged slices in which fast synaptic transmission was blocked by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (10 μM), bicuculline (50 μM), and picrotoxin (50 μM). (−)Baclofen (0.5 μM) and GABA (1 μM) induced equivalent‐sized hyperpolarizations and input resistance decreases. The agonist induced hyperpolarization or current and 4‐AP induced hyperpolarizations or currents (4‐AP induced K‐IPSPs or IPSCs) reversed in sign near the K‐equilibrium potential (EK). The GABAB receptor antagonists, OH‐saclofen (500 μM) and CGP 35348 (100 μM), reduced (−)baclofen responses, and 4‐AP induced K‐IPSPs, suggesting that they were mediated by GABAB receptors. Intracellular tetraethylammonium‐, and extracellular barium‐ions (1 μM) diminished the (−)baclofen induced current and 4‐AP induced K‐IPSCs. Intracellular Cs‐ions blocked the (−)baclofen induced outward current at resting membrane potential but did not grossly affect the inward current recorded at membrane potentials negative to EK. 4‐AP induced inwardly or outwardly directed KIPSCs were not blocked by intracellular Cs‐ions. Extracellular Cs‐ions (5 μM) blocked the (−)baclofen induced inward K‐current, but did not block 4‐AP induced inwardly directed K‐IPSCs. In conclusion, we found differences in the Cs block of K‐channels activated by (−)baclofen or the endogenous transmitter GABA. One reason could be that (−)baclofen predominantly activated extra synaptic GABAB receptors provided that extrasynaptic and subsynaptic receptors couple to different potassium channels. © 1994 Wiley‐Liss, Inc.
5‐HT1a agonist ±‐ 8‐OH‐DPAT modulates basal and stress‐induced changes in medial prefrontal cortical dopamine
Authors: Rasmusson Ann M. , Goldstein Lee E. , Deutch Ariel Y. , Bunney Benjamin S. , Roth Robert H.
Published: December 2004

Serotonergic 5‐HTla agonists have recently been suggested to be effective in the treatment of human anxiety disorders. The neural mechanisms responsible for their clinical efficacy are unknown. In this study we investigated the effects of ±8‐hydroxy‐2(di‐n‐propylamino)tetralin [±8‐OH‐DPAT], a serotonergic,5‐HTIa agonist, on basal and stress‐induced changes in dopamine utilization and release in selected forebrain dopamine terminal fields in the rat. Dopamine utilization and release were respectively assessed by neurochemical analysis of ex vivo brain tissue and by microdialysis in the freely moving animal. Systemic ±8‐OH‐DPAT at doses below 225 μg/kg had no effect in any region except to slightly decrease dopamine utilization in the nucleus accumbens. However, at a dose of 225 μg/kg, ±8‐OH‐DPAT significantly increased basal dopamine utilization and release in the medial prefrontal cortex, while simultaneously decreasing serotonin release in this area. By contrast, the same dose of ±8‐OH‐DPAT decreased extracellular dopamine in the striatum. The effect of ±8‐OH‐DPAT on the response of the dopamine system to mild footshock stress was also assessed. This 5‐HTla agonist diminished the magnitude of footshock‐induced increases in prefrontal cortical dopamine utilization. These data suggest that 5‐HTIa agonists may dose‐dependently modulate both basal and stress‐induced changes in dopamine utilization in the medial prefrontal cortex. The possible relevance of these findings to the observed clinical efficacy of 5‐HT1a agonists in anxiety disorders is discussed. ©1994 Wiley‐Liss, Inc.
Binding of 125I‐iodovinyltetrabenazine to CNS vesicular monoamine transport sites
Authors: Kung Mei‐Ping , Canney Daniel J. , Frederick Dana , Zhuang Zheng , Billings Jeffrey J. , Kung Hank F.
Published: December 2004

Binding characteristics of a novel radioiodinated tetrabenazine (TBZ) analog (iodovinyltetrabenazine; 125I‐TBZ‐Fraction I) were evaluated. In rat striatal homogenates, 125I‐TBZ‐I displayed a pharmacological profile consistent with specific binding to vesicular monoamine transport (VMAT) sites. In vitro autoradiographic studies using rat brain sections; further demonstrated that 125I‐TBZ‐I labeled the regions rich in VMAT sites, and it may be a useful marker for these sites. This novel radioiodinated ligand, with high specific activity and high binding affinity, may provide a powerful tool for the in vitro assessment of neuronal loss in various neurodegenerative diseases. © 1994 Wiley‐Liss, Inc.
Differential effect of MK 801 and scopolamine on c‐fos expression induced by L‐dopa in the striatum of 6‐hydroxydopamine lesioned rats
Authors: Morelli Micaela , Pinna Annalisa , Fenu Sandro , Carta Anna , Cozzolino Alberto , Di Chiara Gaetano
Published: December 2004

In rats with a unilateral 6‐hydroxydopamine lesion of the dopaminergic nigro‐striatal pathway, striatal Dl‐receptor‐stimulated c‐fos expression and turning behavior are positively modulated by D2 receptor stimulation and by blockade of N‐methyl‐D‐aspartate (NMDA) or muscarinic receptors. Combined D1/D2 receptor stimulation by L‐dopa activates c‐fos in a manner not additive with muscarinic receptor blockade by scopolamine. On the other hand, blockade of NMDA receptors by MK 801 reduced c‐fos expression induced by L‐dopa while, depending on the dose of L‐dopa, differentially affecting contralateral turning behavior. The results are interpreted to suggest that D2 receptor stimulation amplifies D1‐receptor‐mediated c‐fos expression by two mechanisms differentially related to muscarinic and NMDA receptors. ©1994 Wilev‐Lisa. Inc.
Alterations in TRH receptors in temporal lobe of schizophrenics: A quantitative autoradiographic study
Authors: Lexow Nedra , Joyce Jeffery N. , Kim Soo Jin , Phillips Jennifer , Casanova Manuel F. , Bird Edward D. , Kleinman Joel E. , Winokur Andrew
Published: December 2004

We utilized quantitative autoradiography to determine the distribution of receptors for thyrotropin‐releasing hormone (TRH) throughout the human temporal lobe and to examine the distribution of these receptors in discrete subregions of the temporal lobe from patients diagnosed premortem with schizophrenia. When compared to non‐neurologic controls, schizophrenic patients demonstrated an increase of 51% in the concentration of TRH receptors in the molecular layer of the dentate gyrus. Within nuclei of the schizophrenic amygdala, marked decreases were found in the central (44%), medial (38%), cortical (36%), accessory cortical (52%), lateral (54%), and medial basal (22%) nuclei. We also examined postmortem brain samples from patients with Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease for alterations in the distribution of TRH receptors. No significant differences from non‐neuropsychiatric controls were noted within the hippocampus in any of these disease states; however, slight alterations were noted in the central and medial basal amygdala in Huntington's disease and in the cortical amygdala in Alzheimer's disease. These disease‐specific findings suggest that TRH may play a role in the neurochemical dysfunction of schizophrenia. © 1994 Wiley‐Liss, Inc.
Glutamatergic antagonists attenuate ability of dopamine uptake blockers to increase extracellular levels of dopamine: Implications for tonic influence of glutamate on dopamine release
Authors: Moghaddam Bita , Bolinao Maria L.
Published: December 2004

Previous in vivo studies reporting a dose‐dependent increase in extracellular dopamine (DA) levels by excitatory amino acid (EAA) antagonists have been interpreted to indicate a lack of tonic excitatory effect exerted by these amino acids on striatal DA release. Alternatively, a tonic excitatory influence on DA release may affect a small fraction of DA terminals, so that blockade of this effect does not make a great enough contribution to the extracellular fluid to be detected by microdialysis. To examine this possibility, the effect of EAA antagonists was assessed by microdialysis in the presence of DA uptake blockers. It was found that in the presence of nomifensine or cocaine, antagonists of either NMDA or AMPA/kainate receptors decreased extracellular DA levels in the striatum. These data suggest that EAAs may exert a tonic facilitatory influence on striatal DA release and/or that endogenous EAAs may potentiate the action of DA uptake blockers through mechanisms that are mediated by EAA receptors. © 1994 Wiley‐Liss, Inc.
NMDA receptors mediate amphetamine‐induced upregulation ofzif/268and preprodynorphin mRNA expression in rat striatum
Authors: Wang John Q. , Daunais James B. , McGinty Jacqueline F.
Published: December 2004

The role of N‐methyl‐D‐aspartate (NMDA) excitatory amino acid receptors in D‐amphetamine (AMPH)‐induced behavioral changes and increased expression of the nuclear transcription factors, c‐fosandzif/268, and preprodynorphin (PPD) mRNA in various regions of rat forebrain was investigated with quantitative in situ hybridization histochemistry. Three hours after a single injection of AMPH (5 mg/kg, i.p.), the mRNA expression ofzif/268, but not c‐fos, in dorsal striatum (caudate nucleus) and cerebral cortex (sensorimotor cortex), and PPD mRNA in dorsal striatum, was upregulated. Pretreatment of rats with MK‐801 (0.5 mg/kg, i.p.) attenuated AMPH‐induced striatal and cortical expression ofzif/268mRNA and striatal expression of PPD mRNA, without affecting the behavioral alterations induced by AMPH. A similar, dose‐dependent suppression of AMPH‐inducedzif/268and PPD mRNA in striatum and cortex was also revealed after systemic administration of (±)‐3‐(2‐carboxypiperazin‐4‐yl)‐propyl‐l‐phosphonic acid (CPP) at doses of 5 and 10 mg/kg. CPP, only at the higher dose, slightly attenuated behavioral activity induced by AMPH. MK‐801 and CPP (at higher dose) alone suppressed basal (constitutive)zif/268mRNA levels in both striatum and cortex regions. No significant effect of either antagonist was found on constitutive expression of striatal PPD mRNA. These studies indicate that NMDA receptors mediate, at least in part, activation ofzif/268and PPD gene expression in striatum and sensorimotor cortex by a single injection of AMPH. Furthermore, NMDA receptor‐mediated gene regulation more likely is involved in long‐term neuronal plasticity to drug exposure than in acute drug effects since NMDA receptor antagonists had little or no effect on the acute behavioral actions of AMPH. © 1994 Wiley‐Liss, Inc.
In vivo binding of [123I]4‐(2′‐methoxy phenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐P‐iodobenzamido‐]ethyl‐piperazine, p‐MPPI, to 5‐HT1A receptors in rat brain
Authors: Kung Mei‐Ping , Zhuang Zhi‐Ping , Frederick Dana , Kung Hank F.
Published: December 2004

The in vivo regional distribution and pharmacological profile of a novel iodinated phenylpiperazine derivative, [123I]p‐MPPI (4‐(2′‐methoxy‐)phenyl‐l‐[2′‐(N‐2″pyridinyl)‐p‐iodobenzamido‐]ethyl‐piperazine), in the rat brain were evaluated for use as a potential in vivo imaging agent for 5‐HT1A receptors. The new ligand penetrated the blood‐brain barrier quickly and efficiently, with 1.2% of the injected dose found in the whole brain at 2 min post i.v. injection. The rate of radioactivity washout was slowest from the hippocampal region, followed by the hypothalamus, cortex, striatum, and cerebellum. The maximum ratio of hippocampus/cerebellum was 3.3 at 30 min postinjection. The specific binding of the radioligand in the hippocampal region, an area rich in 5‐HT1A receptor density, was blocked by pretreatment with a dose of (±) 8‐OH‐DPAT (2 mg/kg, i.v.) or WAY 100635 (1 mg/kg, i.v.), whereas the regional distribution of [123I]p‐MPPI was unaffected by pretreatment with non‐5‐HT1A agents such as ketanserin or haloperidol. Ex vivo autoradiographic studies further confirmed that the specific binding of [123I]p‐ MPPI is associated with 5‐HT1A receptor sites. These results indicate that [123I]p‐MPPI may be a useful candidate for noninvasive single photon emission computed tomography (SPECT) imaging of 5‐HT1A receptor sites in the living human brain. © 1994 Wiley‐Liss, Inc.
Dopamine D2 and D3 receptors in the rat striatum and nucleus accumbens: Use of 7‐OH‐DPAT and [125I]‐Iodosulpride
Authors: Booze Rosemarie M. , Wallace David R.
Published: December 2004

A novel dopamine receptor mRNA transcript has been identified and classified as the D3 receptor subtype. We have examined the binding of the D2/D3‐selective compound [125I]‐Iodosulpride using unlabeled D3‐selective 7‐OH‐DPAT to determine the distribution of D2 and D3 dopamine receptor subtypes in the rat basal forebrain. Use of [125I]‐labeled ligands has significant advantages over [3H]‐labeled compounds for autoradiographic studies, especially for evaluating small brain areas containing low receptor densities. [125I]‐Iodosulpride identified two sites with high affinity (<1 nM) in the presence of (‐)sulpiride (μM; D2+3) or 7‐OH‐DPAT.(10 nM; D3), with a greater density of D2 receptors (twofold) compared to D3 receptors in the striatum. The density of D2 and D3 receptor subtypes displayed a 1:1 ratio in the nucleus accumbens. [125I]‐Iodosulpride with 7‐OH‐DPAT displayed D2 sites, predominately in the striatum. Digital subtraction autoradiography showed the highest levels of D3 binding in the islands of Calleja as well as in the core and shell regions of the nucleus accumbens. In sum, the advantages in using [125I]‐Iodosulpride to label the dopamine receptor subtypes are high specific activity, affinity, and lack of quenching in autoradiographic analyses. Moreover, masking D3 receptors with 7‐OH‐DPAT permitted indirect determination of D3 receptor density and localization using the [125I]‐labeled ligand, without the potential confound of 7‐OH‐DPAT binding to sigma receptors. The colocalization of the D2 dopamine receptors with D3 receptors suggests that unique interactions may exist between the receptor subtypes in the rat basal forebrain region. © 1995 Wiley‐Liss, Inc.
A genetic deficiency in calpastatin and isovalerylcarnitine treatment is associated with enhanced hippocampal long‐term potentiation
Authors: Muller D. , Molinari I. , Soldati L. , Bianchi G.
Published: December 2004

The Milan hypertensive strain (MHS) of rats, in addition to having hypertension, is also characterized by a genetic deficiency in calpastatin, the endogenous inhibitor of calpain. Since this protease has been implicated in long‐term potentiation (LTP), we have investigated whether induction of this form of plasticity was altered in this strain of rats as compared to control animals (Milan normotensive strain, MNS). Progressive induction of LTP by increasing numbers of high frequency trains resulted in a greater degree of potentiation measured with all inducing protocols in MHS as compared with MNS animals. This difference was not related to the hypertension, since another hypertensive strain (the SHR strain) and a segregated Milan hypertensive strain, expressing only the hypertention but not the calpastatin deficiency (the MHNE strain), exhibited an LTP indistinguishable from control rats. Treatment of MHNE rats for 2 months with isovalerylcarnitine, a compound that increases calpain activity, also resulted in a greater amount of LTP induced by high frequency trains. These effects were not related to an enhancement of the NMDA receptor dependent component of responses to burst stimulation. These results are consistent with the idea that conditions under which calpain activation is facilitated are associated with a greater degree of synaptic potentiation. © 1995 Wiley‐Liss, Inc.
Alterations in dopamine uptake sites and D1 and D2 receptors in cats symptomatic for and recovered from experimental parkinsonism
Authors: Frohna Paul A. , Rothblat David S. , Joyce Jeffrey N. , Schneider Jay S.
Published: December 2004

The administration of the neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) to adult cats severely disrupts the dopaminergic innervation of the striatum. Animals display a parkinson‐like syndrome, consisting of akinesia, bradykinesia, postural instability, and rigidity, which spontaneously recovers by 4–6 weeks after the last administration of MPTP. In this study we used quantitative receptor autoradiography to examine changes in DA uptake sites and DA receptors in the basal ganglia of normal, and symptomatic and recovered MPTP‐treated cats.

Consistent with the destruction of the nigrostriatal DA pathway, there was a severe loss of DA uptake sites, labeled with [3H]‐mazindol, in the caudate nucleus (64–82%), nucleus accumbens (44%), putamen (63%), and substantia nigra pars compacta (SNc, 53%) of symptomatic cats. Following behavioral recovery, there were no significant changes in DA uptake site density. Significant increases of [3H]‐SCH 23390 binding to D1 DA receptors were observed in the dorsal caudate (>24%; P < 0.05) of symptomatic cats and in all regions of the caudate‐putamen (>30%; P < 0.05) of recovered animals. [3H]‐SCH 23390 binding in tree substantia nigra pars reticulata was half of that in the striatum and showed no changes in symptomatic or recovered animals. No alterations in the binding of [1251]‐epidepride to D2 receptors was observed in any region of the striatum in either, symptomatic or recovered animals. [1251]‐Epidepride binding in the SNc was decreased by >36% (P < 0.05) following MPTP treatment.

These data show that cats made parkinsonian by MPTP exposure have a significant decrease in the number of DA reuptake sites throughout the striatum and that recovery of sensorimotor function in these animals is not correlated with an increase in the number of striatal reuptake sites. Behavioral recovery, however, does seem to be correlated with a general elevation of Dl receptors throughout the striatal complex. The present data also show that direct correlations between changes in DA receptor regulation after a large DA depleting lesion and behavioral deficits or recovery from those deficits are difficult and that the relationships between DA receptors/transporters and behavior require further study. © 1995 Wiley‐Liss, Inc.
Amphetamine‐Induced time‐dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: A microdialysis study in behaving rats
Authors: Paulson Pamela E. , Robinson Terry E.
Published: December 2004

The purpose of this study was to compare the effects of amphetamine exposure on subsequent amphetamine‐induced changes in behavior and dopamine (DA) release in the dorsal and ventral striatum, as a function of time following the discontinuation of repeated amphetamine treatment. Rats were pretreated with either saline or an escalating‐dose amphetamine regimen, and then received a 0.5 mg/kg amphetamine “challenge” after either 3, 7, or 28 days of withdrawal. Animals tested after 28 days of withdrawal were hypersensitive (sensitized) to the locomotor‐activating effects of amphetamine, and relative to control animals showed a significant enhancement in amphetamine‐stimulated DA release in both the dorsal and ventral striatum, as revealed by in vivo microdialysis. Animals tested after only 3 or 7 days of withdrawal showed neither behavioral sensitization nor enhanced amphetamine‐stimulated DA release. These results establish that time‐dependent changes in behavioral sensitization to amphetamine are associated with time‐dependent changes in amphetamine‐stimulated DA release, and support the hypothesis that persistent sensitization‐related changes in striatal DA neurotransmission contribute to the expression of behavioral sensitization. © 1995 Wiley‐Liss, Inc.
Evidence against differential release of noradrenaline, neuropeptide Y, and dopamine‐β‐hydroxylase from adrenergic nerves in the isolated perfused sheep spleen
Authors: De Potter W. P. , Kurzawa R. , Miserez B. , Coen E. P.
Published: December 2004

The subcellular storage and release of noradrenaline (NA), dopamine‐β‐hydroxylase (DβH), and neuropeptide Y (NPY) was studied in the isolated perfused sheep spleen. Subcellular distribution studies showed a bimodal distribution for NA which was well reflected by DβH and indicated the occurrence of two types of NA storage vesicles. The most dense, presumably large dense‐cored vesicles (LDV), contain both membrane‐bound and soluble DβH the less dense presumably corresponds to small dense‐cored vesicles (SDV) and at least does not contain soluble DβH. The distribution of NPY is extended but shows a peak only at the position of LDV, indicating that LDV contain NPY. Continuous electrical stimulation of the splenic nerve at 2 Hz, 5 Hz, 10 Hz, and 20 Hz or at 20 hz with bursts induced the release of NA, NPY, and DβH. The ratio among these components was constant. The fractional release of DβH and NA was comparable at all frequencies used; that of NPY was 10–20 times lower, suggesting the occurrence of a large nonreleasable NPY pool. The present data argue against a high frequency stimulation or intermittent stimulation‐induced preferential release of NPY from adrenergic neurons and question the concept of frequency‐dependent chemical coding of sympathetic transmission in general. The simplest interpretation of our data is that NA and NPY are released at all frequencies from a single pool. The present findings might signify that only large dense‐cored vesicles are involved in the sympathetic stimulation‐evoked secretion of catecholamines from adrenergic nerve terminals of the isolated sheep spleen. © 1995 Wiley‐Liss, Inc.
Modulation of GABAAreceptor binding in human brain by neuroactive steroids: Species and brain regional differences
Authors: Nguyen Quyen , Sapp Douglas W. , Van Ness Paul C. , Olsen Richard W.
Published: December 2004

Allosteric modulation by neuroactive steroids of radioligand binding sites on the GABAAreceptor complex was demonstrated by autoradiography in vitro in several regions of human brain and the effects compared to those in rat brain. Comparing human and rat, two steroids known to be active in enhancing GABA‐mediated postsynaptic inhibition, 5α‐pregnane‐3α21‐diol‐20‐one (tetrahydro‐deoxycorticosterone, THDOC) and alphaxalone (5α‐pregnane‐3α‐hdyroxy‐11,20‐dione), allosterically inhibited [35S]TBPS binding to the picrotoxin/convulsant site in both species in several regions including the hippocampus. Unlike rat, human brain binding of [3]Hlflunitrazepam to the benzodiazepine site was not enhanced by alphaxalone (at any concentration), but was unaffected in many regions and inhibited in others. Binding of [3H]muscimol to high and low affinity GABA sites were enhanced by both steroids in all tested regions of rat brain, although to varying degrees. However, several lobes of human cortex showed no modulation of muscimol binding by either steroid, and THDOC, but not alphaxolone, inhibited in some areas. Comparing regions, THDOC at high concentrations (10 μM) enhanced in human frontal lobe and primary sensory and motor cortex, with greater effect in deep layers than superficial. This steroid had no effect in other parts of parietal lobe and inhibited muscimol binding in temporal lobe, primary visual cortex, and other parts of occipital lobe. Concentration‐dependence curves for THDOC showed regional variation, e.g., in the hippocampal formation and surrounding neocortex. These regional and species differences are consistent with the existence of multiple GABAAreceptor subtypes that differ in pharmacology. This heterogeneity provides both the opportunity and the difficulty of targeting clinically useful medications such as antiepileptic drugs to the appropriate human brain regions, and the species differences in regional subtype expression suggest caution in use of animal models. © 1995 Wiley‐Liss, Inc.