Comparative study of sulpiride and haloperidol on dopamine turnover in the rat brain

The effects of the neuroleptics, sulpiride and haloperidol, on dopamine (DA) turnover were compared following the acute and chronic administration of these drugs alone or in combination with levodopa or apomorphine. In the acute treatment, the increase in DA metabolites in the striatum and nucleus accumbens was more marked in the haloperidol-treated rats than in the sulpiridetreated rats. Following the additional administration of levodopa, however, the potency of the neuroleptics in elevating DA metabolites was reversed. A low dose of apomorphine induced a marked reduction in the striatal DA metabolite levels by approximately 50%. When rats were pretreated with the neuroleptics, haloperidol was more effective in preventing an apomorphine-induced reduction in DA metabolites. On repeated administration of the neuroleptics, a tolerance occurred in the striatum and nucleus accumbens, but not in the prefrontal cortex. This differential development of tolerance was observed in the different brain regions and with the different drugs administered. These results suggests that the pharmacological mechanism of sulpiride on DA turnover differs from that of haloperidol.     

On the relation between haloperidol-induced alterations in DA release and DA metabolism in rat striatum

Haloperidol (1 mg/kg) was administered to rats pretreated with α-methyl-para-tyrosine-methylester. HCl (αMpT) and the levels of dopamine (DA) as well as HVA and DOPAC were measured in the striatum. While the release of DA was stimulated by haloperidol for at least 60 min, HVA and DOPAC levels were markedly increased only at 30 min, but not at 60, 90, or 120 min, after haloperidol administration. In rats not pretreated with αMpT, on the other hand, a strong increase in metabolite levels was observed between 60 and 120 min after haloperidol administration. It is concluded that a direct relation between DA release and metabolite levels does not exist in the present experiments. DA biosynthesis and processes involved with the clearance of metabolites appear to be important factors in the haloperidol-induced increase in metabolite levels. The relative importance of these three processes remains to be clarified.     

On the Significance of Tyrosine for the Synthesis and Catabolism of Dopamine in Rat Brain: Evaluation by HPLC with Electrochemical Detection

Abstract: A chemical assay of tyrosine (Tyr) in nervous tissue is described. The method is based on a rapidly performed isolation of Tyr on small Sephadex G 10 columns, followed by reverse-phase HPLC in conjunction with amperometric detection. The method permitted the additional quantification of 3,4-dihydroxyphenylalanine, dopamine (DA), and its acidic metabolites. The method was applied to a study of the effects of γ-butyrolactone, haloperidol, haloperidol in combination with amfonelic acid, morphine, NSD 1015, and tyrosine methylester on the concentration of Tyr in the striatum, frontal cortex, hypothalamus, and cerebellum of rat brain. The effect of tyrosine methylester on DA and its acidic metabolites was investigated in the striatum and frontal cortex. Morphine and NSD 1015 were found to increase Tyr levels. γ-Butyrolactone, haloperidol, and haloperidol combined with amfonelic acid decreased the Tyr content in a manner related to their stimulatory effect on DA biosynthesis. These effects were restricted to DA-rich brain areas. It was concluded that during conditions of increased DA biosynthesis, the Tyr pool still possesses a considerable reserve capacity. The results bring into question the concept that brain Tyr is an important additional factor controlling catechol synthesis during increased tyrosine hydroxylase activity.     

Halothane attenuated haloperidol and enhanced clozapine-induced dopamine release in the rat striatum

The effect of halothane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA)) induced by neuroleptics was studied using in vivo microdialysis techniques. Halothane attenuated haloperidol-induced dopamine release and enhanced clozapine-induced dopamine release in the rat striatum.A microdialysis probe was implanted into the right striatum of male SD rats. Rats were given saline or the same volume of 200 microg kg(-1) haloperidol (D(2) receptor antagonist), 10 mg kg(-1) sulpiride (D(2) and D(3) antagonist), or 10 mg kg(-1) clozapine (D(4) and 5-HT(2) antagonist) intraperitoneally with or without 1-h halothane anesthesia (0.5 or 1.5%). Halothane anesthesia did not change the extracellular concentration of DA, but increased the metabolite concentrations in a dose-dependent manner. The increased DA concentration induced by haloperidol was significantly attenuated by halothane anesthesia, whereas the metabolite concentrations were unaffected. Halothane had no effect on the changes in the concentrations of DA or its metabolites induced by sulpiride. The clozapine-induced increases in DA and its metabolites were enhanced by halothane anesthesia.Our results suggest that halothane anesthesia modifies the DA release modulated by antipsychotic drugs in different ways, depending on the effects of dopaminergic or serotonergic pathways.     

Effect of Isolation-Rearing on Conditioned Dopamine Release In Vivo in the Nucleus Accumbens of the Rat

Abstract: Intracerebral microdialysis in conjunction with HPLC coupled to electrochemical detection was used to investigate the effect of isolation-rearing in the rat on extracellular dopamine (DA) and its metabolites in vivo, in the shell region of the nucleus accumbens, in response to footshock and in relation to a conditioned emotional response. Male Lister hooded rats were reared from weaning for 6–8 weeks in either social isolation or groups of five. In the training phase, rats were exposed to a novel environment for 10 min where they experienced mild footshock. Footshock caused an immediate increase in basal extracellular DA levels in both rearing groups relative to control rats. However, the increase in extracellular DA was prolonged in the case of the isolation-reared rats and significantly greater than in group-reared rats. Exposure to the novel environment without shock (control groups) did not significantly alter basal extracellular DA in the nucleus accumbens shell; 140 min later rats were returned to the testing box (contextual stimulus) without receiving footshock. The contextual stimulus increased basal extracellular DA in the nucleus accumbens of both groups of rats with respect to controls; however, this increase was significantly greater and more prolonged in isolates. Extracellular levels of the metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid did not differ between isolation- and group-reared rats, and they were not significantly affected by either footshock or the contextual stimulus. These results suggest that exposure to footshock and a contextual stimulus are associated with increases in basal extracellular DA levels in the nucleus accumbens shell. The results also support evidence in favour of an isolation-induced enhancement in dopaminergic activity in the nucleus accumbens, which probably underlies aspects of the behavioural syndrome associated with isolation.     

Vascular and renal effects of dopamine during extracellular volume expansion: Role of nitric oxide pathway

OBJECTIVE: The aim of the study was to determine the possible role of NO-system activation in vascular and renal effects of the dopaminergic system and the probable interaction between both systems during acute volume expansion in rats. DESIGN AND METHODS: Expanded (10% bw) and non-expanded anaesthetized male Wistar rats were treated with haloperidol, a DA receptor antagonist (3 mg/kg bw, ip). Mean arterial pressure, diuresis, natriuresis, renal plasma flow, glomerular filtration rate, nitrites and nitrates excretion (NOx) were determined. NADPH diaphorase activity was measured using a histochemistry technique in kidney, aorta and renal arteries. NOS activity in kidney and aorta from expanded and non-expanded animals was determined with L-[U14C]-arginine substrate, in basal conditions and after DA (1 microM) administration. RESULTS: The hypotensive effect of L-arg and hypertension induced by L-NAME were not modified by haloperidol. This blocker reverted the increase in diuresis, natriuresis and RPF induced by L-arg in both groups. Dopaminergic blockade induced a decrease in NOx excretion and in NADPH-diaphorase activity in glomeruli, proximal tubule and medullar collecting duct and in endothelium and vascular smooth muscle of renal arteries. DA induced an increase in NOS activity in renal medulla and cortex in both groups, but no changes in the aorta were observed. CONCLUSIONS: Our results suggest that renal DA would be associated with the renal response induced by NO during extracellular volume expansion. NO-system activation would be one of the mechanisms involved in renal DA activity during saline load, but NO appears not to be involved in DA vascular effects.     

Changes caused by haloperidol are blocked by music in Wistar rat

This study sought to evaluate the effect of classical music, using Mozart’s sonata for two pianos (K. 448), on changes in dopamine (DA) levels in the striatal nucleus (SN), prefrontal cortex (PFC) and mesencephalon, and on prolactin (PRL) and corticosterone secretion in adult male Wistar rats. Rats were divided into four groups: (1) control, (2) haloperidol treatment (single dose of 2 mg/kg s.c.), (3) music (two 2-h sessions per day) and (4) haloperidol plus music. Rats were sacrificed 2 h after haloperidol injection. Music prompted a fall in plasma PRL and corticosterone levels in healthy rats (P?P?P?相似文献   

The metabolism of dopamine in rat caudate nucleus can be increased by in vivo “dialysis” perfusion cannulae

The development of dialysis cannula techniques coupled with high performance liquid chromatography and electrochemical detection (HPLC-EC) has provided a means to continuously sample extracellular fluid from deep brain structures $\text{in vivo}$. The present studies show that with HPLC-EC analysis of the acid metabolites of dopamine (DA) and 5-hydroxytryptamine (5-HT) in samples from dialysis cannulae implanted in the caudate nucleus of anaesthetized rats, it is possible to determine the time course of the response of dopamine- and 5-HT containing neurones to administration of monoamine oxidase inhibitors and haloperidol. The tissue concentrations of the DA and 5-HT metabolites were also determined at the conclusion of each individual experiment in both the caudate nucleus containing a cannula and in that without a cannula. In perfusion experiments where no drug was administered the content of the DA metabolites, but not that of the 5-HT metabolite, were significantly elevated in the caudate nucleus containing the cannula as compared with the contralateral tissue. These increases occurred whether the cannula was perfused or not, suggesting that the presence of the cannula may have been causing a lesion which altered the activity of the DA neurones. These results emphasize the importance of tissue analysis in conjunction with the dialysis experiments, especially where perfusion sample contents of the monoamine metabolites are being measured as a reflection of the effects of behavioural manipulation or drug treatment on endogenous neuronal activity.     

Brain monoamines following castration of aggressive muricidal rats

The effect of castration on the levels of brain monoamines and their metabolites has been investigated in rats which became or did not become muricidal following long-term isolation. Fourteen brain areas were explored: olfactory bulbs (OB), olfactory tubercles (OT), septum (Se), striatum (Sr), amygdala (A), thalamus (Th), hypothalamus (Hy), hippocampus (Hi), superior colliculus (SC), inferior colliculus (IC), raphe (Ra), pons-medulla (PM), frontal cortex (FC), temporal cortex (TC) and parietal cortex (PC). Except in the raphe of non muricidal rats and in the striatum of muricidal animals, all other areas examined demonstrate some changes of monoamines neurotransmitter or their metabolites after castration. The strongest changes, always increases, were found in the thalamus. In several brain areas, the changes occurring after castration, differ quantitatively and qualitatively in muricidal and non-muricidal rats.Special issue dedicated to Dr. Claude Baxter.Prof. P. Mandel passed away on October 6th, 1992.     

A comparative study of the neurochemical profiles of remoxipride, raclopride and metoclopramide activity]

Effects of intraperitoneal administration of remoxipride (2.4 mg/kg), raclopride (1.2 mg/kg) and metoclopramide (5 mg/kg) on the concentration of monoamines and metabolites in various brain regions, on the DA and serotonin biosynthesis in the striatum and nucleus accumbens, on the K(+)-stimulated DA release from the isolated striatum, on the extracellular levels of DA and metabolites in the striatum of freely moving rats were studied. Remoxipride and raclopride increase DA turnover, biosynthesis and DA release, studied both in vitro and in vivo. Metoclopramide was shown to be more effective in increasing DA turnover and biosynthesis, while exerted less activity in regard to increasing DA release in vivo and failed to affect release in vitro. Possible neurochemical mechanisms underlying pharmacological effects of these drugs are discussed.     

Effects of iptakalim on extracellular glutamate and dopamine levels in the striatum of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study

In a previous study, we demonstrated that iptakalim (Ipt) significantly ameliorated hypolocomotion and catalepsy induced by haloperidol and rotenone in rats. In order to further understand the mechanism(s), using a rat model of Parkinson's disease (PD) established by unilateral 6-hydroxydopamine (6-OHDA) administration to the substantia nigra pars compacta (SNpc) and reverse microdialysis techniques with high performance liquid chromatography (HPLC), we investigated the effects of Ipt on extracellular levels of glutamate, dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in the striatum of conscious and freely moving rats. The results indicated that unilateral 6-OHDA-lesioned rats have a significantly higher level of extracellular glutamate and a lower level of extracellular DOPAC in the lesioned-side of the striatum, and a lower level of extracellular DA in both sides of the striatum compared to the striatum of control rats. Ipt reduced extracellular glutamate levels in both sides of striatum of the lesioned and control rats in a concentration-dependent manner. Ipt, at lower concentrations (0.01, 0.1, 1 microM), enhanced extracellular DA levels in the lesioned-side striatum of the unilateral 6-OHDA-lesioned rats, while causing no significant changes in the intact side striatum, and even a significant decline in striatum of control rats at higher concentrations of Ipt (10, 100 microM). In addition, Ipt also caused a significant decline in the extracellular DOPAC levels in the lesioned-side striatum of unilateral 6-OHDA-lesioned rats. These data suggest that the major mechanism underlying the ameliorative effects of Ipt on the behavior in 6-OHDA-lesioned rats is the alteration of levels of extracellular neurotransmitters, such as glutamate and DA in the striatum of unilateral 6-OHDA-lesioned rats.     

Isoflurane anesthesia inhibits clozapine- and risperidone-induced dopamine release and anesthesia-induced changes in dopamine metabolism was modified by fluoxetine in the rat striatum: an in vivo microdialysis study

Previously, we have reported that halothane anesthesia increases the extracellular concentrations of dopamine (DA) metabolites in the rat striatum using in vivo microdialysis techniques, and we have suggested that volatile anesthetics affect DA release and metabolism in various ways. The present investigation assesses the effect of isoflurane, widely used in clinical anesthesia, on DA release and metabolism. A microdialysis probe was implanted in the striatum of male Sprague-Dawley rats (n=5-7 per group). After recovery, the probe was perfused with modified Ringer's solution and 40 microl of dialysate were injected into a high performance liquid chromatograph every 20 min. The rats were given saline or the same volume of 10 mg kg(-1) clozapine, risperidone, fluoxetine or citalopram. After the pharmacological treatment, the rats were anesthetized with 1.0% or 2.5% isoflurane for 1h. The data were analyzed using two-way analysis of variance (ANOVA). For each drug with significant (p<0.05) drug-time interactions, the statistical analysis included one-way ANOVA and Newman-Keuls post hoc comparisons. A high concentration of isoflurane (2.5%) anesthesia increased the extracellular concentration of DA metabolites during emergence from anesthesia. The levels of DA metabolites increased in an isoflurane concentration-dependent manner. Isoflurane attenuated DA release induced by clozapine and risperidone. Fluoxetine, but not citalopram, antagonized the isoflurane-induced increase in metabolites. The results of current investigation suggest that isoflurane enhances presynaptic DA metabolism, and that the oxidation of DA might be partially modulated by the activities of the dopaminergic-serotonergic pathway at a presynaptic site in the rat striatum.     

Regulation of nucleus accumbens dopamine release by the dorsal raphe nucleus in the rat

The effects of microinfusingl-glutamate, serotonin (5-HT), (±)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH DPAT; a 5-HT_1A agonist), and muscimol (a GABA_A agonist) into the dorsal raphe nucleus on the extracellular levels of 5-HT, dopamine (DA) and their metabolites in the nucleus accumbens were studied in unanesthetized, freely moving, adult male Wistar rats, using the technique of microdialysis coupled with small-bore HPLC. Administration of 0.75 gl-glutamate produced a 25–50% increase (P<0.05) in the extracellular levels of both 5-HT and DA. On the other hand, infusion of 8-OH DPAT and, to a lesser extent, 5-HT produced a significant (P<0.05) decrease in the extracellular levels of both 5-HT and DA. Muscimol (0.25 or 0.50 g) had little effect on the extracellular concentrations of 5-HT or DA following its administration. In general, the extracellular levels of the major metabolites of 5-HT and DA in the nucleus accumbens were not altered by microinfusion of any of the agents. The data indicate that (a) the 5-HT neurons projecting to the nucleus accumbens from the dorsal raphe nucleus can be activated by excitatory amino acid receptors and inhibited by stimulation of 5-HT_1A autoreceptors, and (b) the dorsal raphe nucleus 5-HT neuronal system may regulate the ventral tegmental area DA projection to the nucleus accumbens.Special issue dedicated to Dr. Morris H. Aprison     

Effect of chloral hydrate on in vivo KCl-induced striatal dopamine release in the rat

The release of striatal dopamine (DA) and its metabolites in response to locally-induced K⁺ depolarization was investigated in vivo in chloral hydrate-anesthetized and freely moving rats. KCl at concentrations of 30, 50, and 100 mM induced significant dose-dependent increases in extracellular DA overflow in both chloral hydrate-anesthetized and freely moving rats (P<0.05). Extracellular levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were decreased. The DA overflow in response to 30 mM KCl stimulation in anesthetized rats was significantly greater than that in freely moving rats (P<0.05). In addition, chloral hydrate anesthesia resulted in a significant decrease in extracellular levels of DOPAC and significant increases in extracellular levels of HVA and 5-HIAA in comparison with freely moving rats (P<0.05). Furthermore, the basal level of extracellular HVA in chloral hydrateanesthetized rats was significantly higher than that in freely moving rats. These results suggest that chloral hydrate anesthesia could have significant effects on the pharmacological response of the striatal dopaminergic neurons.     

Intracerebrally administered (6r)-l-erythro-tetrahydrobiopterin does not affect extracellular levels of dopamine and serotonin metabolites in rat striatum in vivo during measurement by brain micro-dialysis system

By the use of the brain micro-dialysis technique combined with HPLC, the changes in the extracellular levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and a serotonin(5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were examined in the rat striatum before and after intracerebral injection of a vehicle or (6R)-l-erythro-tetrahydrobiopterin (6R-BH₄), the natural form of the cofactor for the tryrosine hydroxylase and tryptophan hydroxylase. No apparent change after the 6R-BH, treatment was found in the levels of DA, DOPAC, HVA and 5-HIAA in the striatal dialysate. In contrast, the levels of total biopterin in both the operated (dialysis probe-implanted) and unoperated striatum of 6R-BH₄-treated rats increased by 23- and 93-fold, respectively, when compared with those of the control, vehicle-treated rats. The results indicate that increased levels of the tetrahydrobiopterin cofactor may not affect the release of DA and the extracellular level of DA and 5-HT metabolites in the physiologically normal brain.     

Effects of testosterone metabolites on copulation and medial preoptic dopamine release in castrated male rats

The medial preoptic area (MPOA) is an important integrative site for male sexual behavior. Dopamine (DA) is released in the MPOA of male rats shortly before and during copulation. The recent presence of testosterone (T) may be necessary for this precopulatory increase in release. Previously, the postcastration loss of copulatory ability mirrored the loss of the DA response to an estrous female, and the restoration of copulation with exogenous T was concurrent with the reemergence of this DA response. The present study investigated the effectiveness of the two major metabolites of T in maintaining copulation and basal and female-stimulated DA levels. Adult male rats were castrated and received daily injections of estradiol benzoate (EB), dihydrotestosterone benzoate (DHTB), EB + DHTB, testosterone propionate (TP), or oil vehicle for 3 weeks. Microdialysis samples were collected from the MPOA during baseline conditions, exposure to an estrous female behind a barrier, and copulation testing. EB + DHTB- and TP-treated animals had normal basal DA levels and showed a precopulatory DA response, and most copulated normally. EB-treated castrates had high basal DA levels, but failed to show a female-stimulated increase; most intromitted, but none ejaculated. DHTB- and oil-treated groups had low basal levels of extracellular DA that did not increase during copulation testing; most failed to mount and none ejaculated. These results suggest that E maintains normal basal levels of extracellular DA in the MPOA, which are sufficient for suboptimal copulation, but that androgen is required for the female-stimulated increase in DA release and for facilitation of ejaculation.     

Extracellular Striatal Dopamine and Its Metabolites During Transient Cerebral Ischaemia

Severe cerebral ischaemia has been repeatedly shown to provoke a massive increase in striatal extracellular dopamine (DA). These experiments were undertaken to determine the duration of the DA increase produced by transient ischaemia, and the fate of the released DA during recirculation. Experiments were performed in anaesthetised rats subjected to 20 min of cerebral ischaemia, followed by 80 min of reperfusion, before cardiac arrest. Measurements of catechols were made in the striatum using in vivo differential pulse voltammetry (DPV), each 4 min, throughout the experiment and for 60 min after cardiac arrest. DPV data were substantiated with intracerebral dialysis; 20-min dialysate samples were analysed for DA and homovanillic acid (HVA) using HPLC. In 6 of 11 rats, ischaemia induced a massive DA release in the striatum, resulting in a marked increase in extracellular levels (350-1,200%), which persisted throughout ischaemia. DPV and intracerebral dialysis demonstrated that DA was totally cleared from the extracellular space within minutes of reperfusion, whereas both its acidic metabolites (3,4-dihydroxyphenylacetic acid and HVA) increased slightly. These results indicate that DA released during 20-min ischaemia is rapidly cleared during reperfusion, mainly via reuptake. In the five other rats, only a relatively small and transient increase in the DPV catechol peak was detectable, cleared before the end of ischaemia, probably reflecting less severe ischaemia; small or no changes were detectable in the corresponding dialysate. The latter data suggest that different change(s) in the nigrostriatal dopaminergic system may occur, according to the severity of ischaemia.     

Microdialysis Study of Modification of Hypothalamic Neurotransmitters in Streptozotocin-Diabetic Rats

Abstract: Neurochemical changes in the ventromedial hypothalamus (VMH) after a single intravenous injection of streptozotocin were examined, using in vivo brain microdialysis under free-moving conditions. Although streptozotocin-induced diabetes produced significant decreases in extracellular concentrations of noradrenaline (NA), serotonin (5-HT), and their metabolites in the VMH, the ratios of 3-methoxy-4-hydroxyphenylglycol/NA and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT were increased. Experimental diabetes led to a pronounced increase in extracellular GABA, which correlated strongly with the decrease in dialysate levels of NA, and to a smaller extent with that of 5-HT. A modification of dopamine (DA) metabolism was induced in the VMH of diabetic rats, whereas there was no change in dialysate DA levels. Daily injections of insulin were able to restore their levels to normal in the areas tested in the microdialysis study. The equal increases in dialysate 5-HT and 5-HIAA and the better restoration of the 5-HIAA/5-HT ratio after insulin therapy indicate that serotonergic activity may depend on the levels of circulating insulin more than on noradrenergic activity. Circulating NA was reduced in streptozotocin-diabetic rats, suggesting that the diabetes-induced reduction in sympathetic activity is accompanied by decreases in NA, or 5-HT, or both, in the VMH.     

Spontaneous and septal models of muricidal behavior: regional activity of enzymes regulating angiotensin and bradykinin metabolism in the brain

Spontaneously muricidal rats (SMR) were selected from a group of white male rats. In the remaining animals muricide was induced by the local electrolyte damage of the brain septal area. Both muricidal models had different physiological indexes of aggressive reactions. In SMR a significant decrease in angiotensin-converting enzyme activity was detected in the midbrain and thalamus-hypothalamus areas. In the group of operated muricidal ("septal") rats alterations in angiotensin-converting enzyme activity have been revealed in none of the brain areas examined. The increase in total kinin-destroying activity in the pituitary, cerebellum, striatum and thalamus-hypothalamus areas was detected. The results indicate neurochemical specificity of brain angiotensin II and kinins in the regulation of different muricidal models.     

GABAA Receptor Blockade in the Anterior Ventral Tegmental Area Increases Extracellular Levels of Dopamine in the Nucleus Accumbens of Rats

Abstract: Previously, it was shown that microinfusion of the GABA_A antagonist picrotoxin into the anterior ventral tegmental area (VTA) is reinforcing. It was hypothesized that this reinforcing effect of picrotoxin in the anterior VTA is mediated, at least in part, by the activation of the mesoaccumbens dopamine (DA) system. The objective of the present study was to determine if blockade of GABA_A receptors in the anterior VTA can increase extracellular levels of DA in the nucleus accumbens (ACB), using an in vivo microdialysis technique in freely moving rats. Concentrations of picrotoxin (40, 80, and 160 µ M ) that had previously been shown to produce a reinforcing effect increased the extracellular levels of DA and its major metabolites in the ACB. The increased extracellular DA levels induced by intra-VTA injection of picrotoxin was markedly attenuated by coadministration with the GABA_A agonist muscimol, whereas intra-VTA injection of muscimol alone did not have an apparent effect on extracellular DA levels in the ACB. Microinjection of another GABA_A antagonist, bicuculline, into the anterior VTA also increased the extracellular release of DA in the ACB. These results suggest that DA neurons projecting from the anterior VTA to the ACB are tonically inhibited by GABA through its actions at the GABA_A receptors.