Glutamate In Nucleus Accumbens Research Articles

Effects of endogenous glutamate on extracellular concentrations of taurine in striatum and nucleus accumbens of the awake rat: involvement of NMDA and AMPA/kainate receptors.

Using microdialysis, the effects of endogenous glutamate on extracellular concentrations of taurine in striatum and nucleus accumbens of the awake rat were investigated. The glutamate uptake inhibitor L-transpyrrolidine-2,4-dicarboxylic acid (PDC) was used to increase the extracellular concentration of glutamate. PDC (1, 2 and 4mM) produced a dose-related increase of extracellular concentrations of glutamate and taurine in striatum and nucleus accumbens. Increases of extracellular taurine were significantly correlated with increases of extracellular glutamate, but not with PDC doses, which suggests that endogenous glutamate produced the observed increases of extracellular taurine in striatum and nucleus accumbens. The role of ionotropic glutamate receptors on the increases of taurine was also studied. In striatum, perfusion of the antagonists of NMDA and AMPA/kainate glutamate receptors attenuated the increases of extracellular taurine. AMPA/ kainate, but not NMDA receptors, also reduced the increases of extracellular taurine in nucleus accumbens. These results suggest that glutamate-taurine interactions exist in striatum and nucleus accumbens of the awake rat.

Glutamate Transmission in the Nucleus Accumbens Mediates Relapse in Cocaine Addiction

Elevated dopamine transmission in the nucleus accumbens is thought to be a primary mediator of addiction to cocaine. However, repeated exposure to cocaine is associated with the recruitment of glutamate transmission. This poses the possibility that the behaviors characterizing cocaine addiction, such as craving-induced relapse, may not be preferentially mediated by dopamine transmission. An animal model of relapse was used to demonstrate that glutamate, and not dopamine transmission in the nucleus accumbens, is a primary mediator of cocaine-induced reinstatement of drug-seeking behavior. Reinstatement was produced by a systemic injection of cocaine or by the microinjection of the glutamate receptor agonist AMPA or dopamine into the nucleus accumbens. It was found that microinjection of an AMPA receptor antagonist into the nucleus accumbens blocked reinstatement by all compounds, whereas a dopamine receptor antagonist was effective only in blocking reinstatement by intra-accumbens dopamine administration. These data suggest an important role for nucleus accumbens glutamate and not dopamine transmission in cocaine-induced relapse to drug-seeking behavior.

Nicotine stimulation of extracellular glutamate levels in the nucleus accumbens: neuropharmacological characterization.

In the present study, we have characterized the neuropharmacological regulation of nicotine-induced increases in extracellular nucleus accumbens glutamate levels. Sprague-Dawley rats were stereotaxically implanted with 2 mm microdialysis probes in the nucleus accumbens and on the following day in vivo microdialysis experiments were performed in awake, freely moving animals. An acute dose of nicotine (0.3-0.6 mg/kg, s.c.) produced an increase in nucleus accumbens glutamate levels with a maximal increase of approximately 50% following the higher dose. No changes in nucleus accumbens aspartate levels were found. The increase in glutamate levels following nicotine (0.3 mg/kg, s.c.) was blocked by mecamylamine (1 mg/kg, i.p. ) but not by haloperidol (0.2 mg/kg, i.p.) pretreatment. Local perfusion of artificial cerebrospinal fluid (CSF) without calcium did not alter nicotine (0.3 mg/kg, s.c.) stimulation of glutamate levels. Local perfusion with a selective blocker for the GLT-1 glutamate transporter, dihydrokainic acid (DHKA) (10(-4) M), had no effect, while local perfusion with a nonselective glutamate transporter blocker, L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) (10(-4) M), blocked nicotine (0.3 mg/kg, s.c.) stimulation of glutamate levels. In animals previously dopamine denervated by local injections of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens, nicotine (0.3 mg/kg, s.c.) stimulation of glutamate levels was enhanced vs. sham-lesioned animals. These findings demonstrate a novel form of nucleus accumbens glutamate release that is dopamine- and calcium-independent. The ability of PDC to block the effects of nicotine suggest that a glutamate transporter may be involved in mediating the stimulation of glutamate release.

Effects of Aging on the Interaction Between Glutamate, Dopamine, and GABA in Striatum and Nucleus Accumbens of the Awake Rat

The aim of the present study was to investigate, using microdialysis, the effects of aging on the glutamate/dopamine/GABA interaction in striatum and nucleus accumbens of the awake rat. For that, the effects of an increase of the endogenous concentration of glutamate on the extracellular concentration of dopamine and GABA in striatum and nucleus accumbens of young (2-4 months), middle-aged (12-14 months), aged (27-33 months), and very aged (37 months) male Wistar rats were studied. Endogenous extracellular glutamate was selectively increased by perfusing the glutamate uptake inhibitor L-trans-pyrrolidine-3,4-dicarboxylic acid (PDC) through the microdialysis probe. In young rats, PDC (1, 2, and 4 mM) produced a dose-related increase of dialysate concentrations of glutamate in both striatum and nucleus accumbens. PDC also increased dialysate dopamine and GABA in both structures. These increases were significantly correlated with the increases of glutamate but not with the PDC dose used, which strongly suggests that the increases of dopamine and GABA were produced by glutamate. In striatum, there were no significant differences in the dopamine/glutamate and GABA/glutamate correlations between young and aged rats. This means that the effects of glutamate on dopamine and GABA do not change during aging. On the contrary, in the nucleus accumbens of aged rats, the increases of dopamine, when correlated with the increases of glutamate, were significantly lower than in young rats. Moreover, the ratio of dopamine to glutamate increases at maximal increases of glutamate was negatively correlated with aging. On the contrary, the ratio of GABA to glutamate increases in nucleus accumbens was positively correlated with aging, which suggests that the effects of endogenous glutamate on GABA tend to be higher in the nucleus accumbens of aged rats. The findings of this study suggest that aging changes the interaction between endogenous glutamate, dopamine, and GABA in nucleus accumbens, but not in striatum, of the awake rat.

A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior

This study investigated the effect of ionotropic glutamate receptor agonist or antagonist administration into the nucleus accumbens on the maintenance of cocaine self-administration and the reinstatement of cocaine-seeking behavior. The stimulation of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or N-methyl- d-aspartate glutamate receptors in the nucleus accumbens with either α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or 1-aminocyclobutane- cis-1,3-dicarboxylic acid, respectively, decreased the number of cocaine-reinforced responses, suggesting an enhancement in the rewarding properties of cocaine. In contrast, blockade of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors with N-methyl- d-aspartate, or N-methyl- d-aspartate receptors with dizocilpine maleate or 2-amino-5-phosphonovaleric acid had no selective effect on the maintenance of cocaine self-administration. Following one week of extinction from the reinforcing cue of the drug-paired lever, both α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid and 1-aminocyclobutane- cis-1,3-dicarboxylic acid treatment in the nucleus accumbens reinstated cocaine-seeking behavior. However, α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid treatment increased responding only on the drug-paired lever, while 1-aminocyclobutane- cis-1,3-dicarboxylic acid increased responding on both the drug-paired and non-drug-paired levers. These results suggest that stimulation of glutamate receptors in the nucleus accumbens augments the reinforcing effect of cocaine, yet glutamate transmission is not required to maintain cocaine self-administration. In addition, increased glutamate transmission in the nucleus accumbens may be involved in facilitating the relapse to cocaine-seeking behavior.

Acamprosate Decreases the Hypermotility During Repeated Ethanol Withdrawal

One of the known behavioral actions of acamprosate is to prevent relapse in weaned alcoholics. However, the mechanism underlying this effect remains unclear. In this study, the motility of Wistar male rats, which were either alcoholized by ethanol inhalation or simultaneously alcoholized and treated orally by acamprosate (400 mg/kg/day) for 4 weeks, was measured during four episodes of the ethanol withdrawal. The concentrations of excitatory and inhibitory amino acids were also assayed by the microdialysis technique with OPA/BME precolumn derivatisation and electrochemical detection in the nucleus accumbens. Acamprosate reduces both the motility and the glutamate microdialysate content during the first 12 h of ethanol withdrawal in comparison to the alcoholized untreated group. The basal concentration of the sulfonated amino acid taurine increased significantly in alcoholized acamprosate-treated rats compared to alcoholized untreated rats. These results suggest that acamprosate is able to reduce the hypermotility during ethanol withdrawal syndrome directly by reducing the nucleus accumbens glutamate concentration or indirectly by increasing the taurine and GABA brain level.

Effect of Precipitated Withdrawal on Extracellular Glutamate and Aspartate in the Nucleus Accumbens of Chronically Morphine-Treated Rats: An In Vivo Microdialysis Study

Excitatory amino acids release during morphine or naloxone administration was studied in rats. Microdialysis in freely moving animals and capillary electrophoresis with laser-induced fluorescence detection were used to measure several amino acids including glutamate and aspartate in the extracellular fluid at the nucleus accumbens. Perfusion with a calcium-free Ringer’s solution decreased glutamate and aspartate in nucleus accumbens dialysates to 35% of its baseline levels, suggesting partial synaptic origin of these amino acids. The first morphine injection decreased glutamate and aspartate to 50% of its baseline level. After repeated morphine injections this effect disappeared, suggesting tolerance. Naloxone injections to morphine-dependent rats increased 300% glutamate and aspartate release; these experiments suggest that excitatory amino acid release in the nucleus accumbens might play a role in morphine withdrawal.

Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: studies on the involvement of dopamine.

The effects of cocaine and d-amphetamine on extracellular glutamate and aspartate levels in the nucleus accumbens, prefrontal cortex, and striatum were studied by in vivo microdialysis in awake, freely moving rats. In the nucleus accumbens, glutamate levels were stimulated by cocaine (15-30 mg/kg, i.p.), GBR 12909 (15 mg/kg, i.p.), and d-amphetamine (2 mg/kg, i.p.), while aspartate levels were not affected. The increase in nucleus accumbens glutamate levels following cocaine (30 mg/kg) was calcium-dependent and was blocked by pretreatment with dopamine antagonists; haloperidol (0.2 mg/kg, i.p.), SCH 23390 (0.02 mg/kg, i.p.), and raclopride (1 mg/kg, i.p.), as well as local 6-OHDA lesions of the nucleus accumbens. In the prefrontal cortex, glutamate levels were stimulated by both cocaine (15-30 mg/kg, i.p.) and d-amphetamine (2 mg/kg, i.p.), while aspartate levels were moderately stimulated by d-amphetamine only. The increase in prefrontal cortex glutamate levels following cocaine (30 mg/kg) was calcium-dependent and was blocked by pretreatment with SCH 23390 (0.02 mg/kg, i.p.), but not haloperidol (0.2 mg/kg, i.p.) or raclopride (1 mg/kg, i.p.). In the striatum, glutamate and aspartate levels were not affected by either cocaine (15-30 mg/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). These findings demonstrate that stimulants enhance glutamate release in limbic brain structures, nucleus accumbens, and prefrontal cortex, but not extrapyamidal brain structures, striatum. Furthermore, the increase in glutamate release in the nucleus accumbens may be mediated by dopamine.

The accumbens: beyond the core-shell dichotomy.

This article highlights recent discoveries related to the accumbens and closely associated structures, with special reference to their importance in neuropsychiatry. The development of "striatal patches" in the accumbens is reviewed in a series of pictures. Neuronal ensembles are discussed as potentially important functional-anatomical units. Attention is also drawn to recent discoveries related to the neuronal circuits that the primate accumbens establishes with the mesencephalic dopamine system. On the basis of histological and neurochemical differences, the accumbens has been divided into core and shell compartments. In the context of this article, the shell, which is an especially diversified part of the accumbens, is the subject of special attention because of its close relation to the extended amygdala and distinctive response to antipsychotic and psychoactive drugs.

Acute and Repeated Systemic Amphetamine Administration: Effects on Extracellular Glutamate, Aspartate, and Serine Levels in Rat Ventral Tegmental Area and Nucleus Accumbens

Recent work indicates an important role for excitatory amino acids in behavioral sensitization to amphetamine. We therefore examined, using in vivo microdialysis in awake rats, the effects of amphetamine on efflux of glutamate, aspartate, and serine in the ventral tegmental area and nucleus accumbens, brain regions important for the initiation and expression of amphetamine sensitization, respectively. Water-pretreated and amphetamine-pretreated rats were compared to determine if sensitization altered such effects. In both brain regions, Ca2+-dependent efflux of glutamate accounted for approximately 20% of basal glutamate efflux. A challenge injection of water or 2.5 mg/kg of amphetamine did not significantly alter glutamate, aspartate, or serine efflux in the ventral tegmental area or nucleus accumbens of water- or amphetamine-pretreated rats. However, 5 mg/kg of amphetamine produced a gradual increase in glutamate efflux in both regions that did not reverse, was observed in both water- and amphetamine-pretreated rats, and was prevented by haloperidol. Although increased glutamate efflux occurred with too great a delay to mediate acute behavioral responses to amphetamine, it is possible that repeated augmentation of glutamate efflux during repeated amphetamine administration results in compensatory changes in levels of excitatory amino acid receptors in the ventral tegmental area and nucleus accumbens that contribute to development of expression of amphetamine sensitization.

Evidence for sensitization of cocaine-induced nucleus accumbens glutamate release.

Cocaine-stimulated glutamate release in the nucleus accumbens was studied following chronic cocaine or saline pretreatment in order to determine whether this effect was sensitized in rats showing augmented dopamine release, locomotor and stereotypy responses. Rats were pretreated with cocaine (30 mg kg-1) or saline for 5 consecutive days and were tested with cocaine (15 mg kg-1) after a 10-day withdrawal period. Cocaine-induced glutamate release, dopamine release, horizontal locomotor activity and stereotypy were monitored simultaneously in animals undergoing in vivo microdialysis in the nucleus accumbens. The basal levels of extracellular glutamate and dopamine, as well as locomotor activity, were not different between cocaine- and saline-pretreated groups. Following cocaine injection the increase in glutamate release, dopamine release, locomotor activity and stereotypy were greater in the cocaine-pretreated animals. These results show that cocaine-stimulated glutamate release in the nucleus accumbens is sensitized following chronic cocaine pretreatment.

Extracellular glutamate in the nucleus accumbens during a conditioned emotional response in the rat

In vivo microdialysis combined with HPLC-EC analysis was used to monitor extracellular glutamate and GABA in the medial nucleus accumbens of Lister hooded rats during acquisition and expression of a conditioned emotional response. Footshock paired with tone (acquisition) of conditioned emotional response) causes a significant decrease in extracellular glutamate during the period of footshock followed by a marked, but short lasting increase when the rats return to their home cage. Expression of the conditioned emotional response on exposure to the contextual cue produces no change in glutamate during exposure to the contextual cue, but a short lasting increase after. Thus, both the conditioned emotional response and footshock are associated with marked, but short lasting, increases in extracellular glutamate in the nucleus accumbens which, in both cases, occurred after the aversive stimuli, i.e., when the rats are returned to their home cage. In contrast, when control rats are exposed to the testing box without giving footshock there is an increase in extracellular glutamate during the exposure period and this is accompanied by exploratory behaviour. The conditioned emotional response (contextual cue), footshock and exposure of the control rats to the test box all resulted in increased extracellular GABA during exposure to the test situation. These results suggest that increases in extracellular glutamate in the medial nucleus accumbens caused by the conditioned emotional response or footshock are probably associated with relief from, rather than response to dange.

ACUTE ETHANOL INCREASES TAURINE BUT NEiTHER GLUTAMATE NOR GABA IN THE NUCLEUS ACCUMBENS OF MALE RATS: A MICRODIALYSIS STUDY

The effects of acute intraperitoneal administration of ethanol (1-3 g/kg body wt) on the extracellular concentrations of glutamate (GLU), taurine (TAU) and gamma-aminobutyric acid (GABA) in rat brain nucleus accumbens were studied by the microdialysis technique coupled to HPLC-EC detection. Levels of GLU and GABA were not affected by ethanol, whereas those of TAU were increased by doses of the drug of 2-3 g/kg.

Effects of repeated administration of a high dose of methamphetamine on dopamine and glutamate release in rat striatum and nucleus accumbens

We examined effects of a high dose of methamphetamine (MA) (4.02 mg free base/kg, s.c., at 2-h intervals, 4 injections) on extracellular concentrations of monoamines such as dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) and those of glutamate and other several amino acids in rat striatum (ST) and nucleus accumbens (NA) using in vivo microdialysis. Five days after the microdialysis, tissue concentrations of monoamines were measured. The toxic dose of MA markedly increased extracellular concentrations of DA, and decreased those of DOPAC, HVA and 5-HIAA in both ST and NA. Magnitude of the increase in DA release was not different between ST and NA. Extracellular concentrations of glutamate showed a gradual increase in ST, but not in NA, while other amino acids showed no changes in both ST and NA. Tissue concentrations of serotonin (5-HT) and 5-HIAA were decreased to 43–58% of control values in both ST and NA, whereas those of DA, DOPAC and HVA showed 43–54% decrease in ST but no changes in NA. These data suggest that the marked increase of DA release is not directly related to the MA-induced dopaminergic neurotoxicity. The increase in glutamate release found only in ST may be related to the dopaminergic damage in ST. It may be that enhanced release in DA and glutamate act synergistically to cause the dopaminergic neurotoxicity in ST. However, enhancement in glutamate release did not appear to be essential for the MA-induced serotonergic neurotoxicity.

Subcortical excitatory amino acid levels after acute and subchronic administration of typical and atypical neuroleptics

The effects of three atypical neuroleptic compounds, clozapine, sulpiride, and (−)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine ((−)-3-PPP) were compared to the effects of haloperidol and saline on excitatory amino acid levels in the rodent nucleus accumbens and corpus striatum after acute (1 day) and subchronic (28 days) treatment. Equivalent doses of each drug were determined by assessing their in vivo displacement of [ 3H]spiperone binding in the nucleus accumbens and corpus striatum. After acute treatment, all three atypical neuroleptics, but not haloperidol, produced a significant decrease in nucleus accumbens glutamate concentrations. Acute haloperidol treatment significantly elevated glutamate concentrations in the corpus striatum when compared to all three atypical drugs. After subchronic treatment, (−)-3-PPP significantly increased glutamate concentrations in the nucleus accumbens when compared to the effects of haloperidol and clozapine. There were no major between-group differences in glutamate levels after subchronic treatment in the corpus striatum. The effects of acute and subchronic neuroleptic administration on aspartate levels in the nucleus accumbens and corpus striatum were highly variable. These findings indicate that atypical and typical neuroleptics may alter subcortical excitatory amino acid levels in a site-specific manner.

GABA and nucleus accumbens glutamate neurotransmission modulate ethanol self-administration in rats.

Annals of the New York Academy of SciencesVolume 654, Issue 1 p. 502-505 GABA and Nucleus Accumbens Glutamate Neurotransmission Modulate Ethanol Self-Administration in Ratsa STEFANIE RASSNICK, Corresponding Author STEFANIE RASSNICK Department of Neuropharmacology The Scripps Research Institute 10666 North Torrey Pines Road La Jolla, California 92037Author to whom correspondence should be addressed.Search for more papers by this authorELIZABETH D'AMICO, ELIZABETH D'AMICO San Diego State University San Diego, California 92120Search for more papers by this authorEDWARD RILEY, EDWARD RILEY San Diego State University San Diego, California 92120Search for more papers by this authorLUIGI PULVIRENTI, LUIGI PULVIRENTI Department of Neuropharmacology The Scripps Research Institute 10666 North Torrey Pines Road La Jolla, California 92037Search for more papers by this authorWALTER ZIEGLGÄNSBERGER, WALTER ZIEGLGÄNSBERGER Max-Planck-Institute for Psychiatry 800 München 40 GermanySearch for more papers by this authorGEORGE F. KOOB, GEORGE F. KOOB Department of Neuropharmacology The Scripps Research Institute 10666 North Torrey Pines Road La Jolla, California 92037Search for more papers by this author STEFANIE RASSNICK, Corresponding Author STEFANIE RASSNICK Department of Neuropharmacology The Scripps Research Institute 10666 North Torrey Pines Road La Jolla, California 92037Author to whom correspondence should be addressed.Search for more papers by this authorELIZABETH D'AMICO, ELIZABETH D'AMICO San Diego State University San Diego, California 92120Search for more papers by this authorEDWARD RILEY, EDWARD RILEY San Diego State University San Diego, California 92120Search for more papers by this authorLUIGI PULVIRENTI, LUIGI PULVIRENTI Department of Neuropharmacology The Scripps Research Institute 10666 North Torrey Pines Road La Jolla, California 92037Search for more papers by this authorWALTER ZIEGLGÄNSBERGER, WALTER ZIEGLGÄNSBERGER Max-Planck-Institute for Psychiatry 800 München 40 GermanySearch for more papers by this authorGEORGE F. KOOB, GEORGE F. KOOB Department of Neuropharmacology The Scripps Research Institute 10666 North Torrey Pines Road La Jolla, California 92037Search for more papers by this author First published: June 1992 https://doi.org/10.1111/j.1749-6632.1992.tb26013.xCitations: 40 a Research was supported by grants provided by the National Institute on Alcohol Abuse and Alcoholism: AA05297 and AA06420, and The Alcoholic Beverage Medical Research Foundation. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume654, Issue1The Neurobiology of Drug and Alcohol AddictionJune 1992Pages 502-505 RelatedInformation

Nucleus accumbens NMDA antagonist decreases locomotor activity produced by cocaine, heroin or accumbens dopamine, but not caffeine

Glutamatergic afferents to the nucleus accumbens (NAC) have been suggested to modulate psychostimulant-induced locomotor activation. The purpose of this study was 1) to determine the importance of nucleus accumbens N-methyl-D-aspartate (NMDA) glutamate receptors in the control of psychostimulant-induced locomotion, 2) to determine whether NMDA receptor modulation of psychostimulant-induced locomotion occurs presynaptic to or postsynaptic to NAC dopamine terminals, and 3) to determine whether NMDA receptors also modulate opiate- and caffeine-induced locomotor activation. For this purpose, rats treated with cocaine (10 mg/kg IP), dopamine (20 micrograms directly into the NAC), heroin (0.5 mg/kg SC), or caffeine (10 mg/kg SC) were challenged with intra-NAC microinfusion of 2-amino-5-phosphonovaleric acid (APV), a selective NMDA receptor antagonist. APV reduced locomotor activation induced by cocaine, heroin and intra-NAC dopamine, but not caffeine. These results suggest that NAC glutamate modulates psychomotor stimulation at the level of the NAC through an interaction with the integrated output of this region.

Self-administration of drugs of abuse in rats: Nucleus accumbens glutamate modulates mesolimbic dopamine function

Self-administration of drugs of abuse in rats: Nucleus accumbens glutamate modulates mesolimbic dopamine function