The Prefrontal Cortex Regulates the Basal Release of Dopamine in the Limbic Striatum: An Effect Mediated by Ventral Tegmental Area

Abstract: The present study examined whether the prefrontal cortex (PFC) exerts a tonic control over the basal release of dopamine in the limbic striatum and whether this control is mediated by glutamatergic afferents to the dopamine cell body or terminal regions. Using intracerebral microdialysis in freely moving rats, it was demonstrated that application of tetrodotoxin in the contralateral PFC significantly decreased the release of dopamine in the medial striatum. Conversely, blockade of the tonic inhibitory GABAergic input in the PFC with bicuculline increased the release of dopamine in the medial striatum. Application of excitatory amino acid receptor antagonists into the striatum, while bicuculline was perfused in the PFC, did not affect the bicuculline-evoked dopamine increase in the striatum. However, infusion of tetrodotoxin or excitatory amino acid receptor antagonists into the ventral tegmental area, a region containing dopamine cell bodies that project to the medial striatum, blocked the stimulation of striatal dopamine release induced by infusion of bicuculline into the PFC. These data demonstrate that the basal output of dopamine terminals in the medial striatum is under a tonic excitatory control of the PFC. Furthermore, this control occurs primarily through glutamatergic projections to the dopamine cell body area rather than the terminal regions.     

Cortical Regulation of Subcortical Dopamine Release: Mediation via the Ventral Tegmental Area

Abstract: In vivo microdialysis was used to determine the extent to which ionotropic glutamate receptors in the ventral tegmental area (VTA) regulate dopamine release in the nucleus accumbens. Coapplication of 2-amino-5-phosphonopentanoic acid (AP5; 200 µ M ) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 µ M ) to the VTA via reverse dialysis decreased extracellular concentrations of dopamine in the nucleus accumbens by ∼30%. In accordance with previous results, electrical stimulation of the prefrontal cortex increased dopamine release by 60%. Application of AP5 and CNQX to the VTA during cortical stimulation blocked the effect of stimulation on dopamine release. These results indicate that ionotropic glutamate receptors in the VTA are critically involved in basal and evoked dopamine release in the nucleus accumbens and suggest that a glutamatergic projection from the prefrontal cortex regulates the activity of dopaminergic neurons in the VTA.     

Eating-Induced Dopamine Release from Mesolimbic Neurons Is Mediated by NMDA Receptors in the Ventral Tegmental Area: A Dual-Probe Microdialysis Study

Abstract: This study was aimed at identifying the neuronal pathways that mediate the eating-induced increase in the release of dopamine in the nucleus accumbens of the rat brain. For that purpose, a microdialysis probe was implanted in the ventral tegmental area and a second probe was placed in the ipsilateral nucleus accumbens. Receptor-specific compounds acting on GABA_A (40 µ M muscimol; 50 µ M bicuculline), GABA_B (50 µ M baclofen), acetylcholine (50 µ M carbachol), NMDA [30 µ M (±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP)], and non-NMDA [300 µ M 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] receptors were infused into the ventral tegmental area by retrograde dialysis, whereas extracellular dopamine was recorded in the ipsilateral nucleus accumbens. Intrategmental infusion of muscimol or baclofen decreased extracellular dopamine in the ipsilateral nucleus accumbens; CPP and CNQX were without effect, and bicuculline and carbachol increased dopamine release. During infusion of the various compounds, food-deprived rats were allowed to eat for 10 min. The infusions of muscimol, bicuculline, baclofen, carbachol, and CNQX did not prevent the eating-induced increase in extracellular dopamine in the nucleus accumbens. However, during intrategmental infusion of CPP, the eating-induced increase in extracellular dopamine in the nucleus accumbens was suppressed. These results indicate that a glutamatergic projection to the ventral tegmental area mediates, via an NMDA receptor, the eating-induced increase in dopamine release from mesolimbic dopamine neurons.     

Characterization of Excitatory Amino Acid Modulation of Dopamine Release in the Prefrontal Cortex of Conscious Rats

Abstract: The effect of various classes of excitatory amino acid agonists on the release of dopamine in the medial prefrontal cortex (PFC) of awake rats was examined using intracerebral microdialysis. Local infusion of 20 µ M α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), through the microdialysis probe, produced a significant increase of more than twofold in extracellular levels of dopamine. Application of 100 µ M AMPA increased these levels nearly 15 fold. The AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (50 µ M ) blocked the increase in dopamine release produced by 20 µ M AMPA. Local infusion of kainate at concentrations of 5 and 20 µ M increased dopamine release by nearly 150 and 500%, respectively. Local application of CNQX (50 µ M ) before 20 µ M kainate significantly attenuated the stimulatory effect of kainate on dopamine levels. In contrast to AMPA and kainate, infusion of N -methyl- d -aspartate (NMDA) at 20 or 100 µ M did not increase dopamine release. In fact, a trend toward a decrease in dopamine release was evident after 100 µ M NMDA. The present study indicates that the in vivo release of dopamine in the PFC is facilitated by AMPA and kainate receptors. This modulation is more profound than that previously reported in the basal ganglia. The lack of an excitatory effect of NMDA is in agreement with recent reports that the NMDA receptor may inhibit indirectly dopaminergic neurotransmission in the PFC.     

Increased Neostriatal Tyrosine Hydroxylation During Stress: Role of Extracellular Dopamine and Excitatory Amino Acids

Abstract: We examined the regulation of neostriatal tyrosine hydroxylation during acute stress, testing the hypothesis that excitatory amino acids (EAAs) contribute to the stress-evoked increase in dopamine (DA) synthesis. Dialysis probes implanted into neostriatum permitted delivery of drugs and sampling of extracellular fluid. Rats were exposed to 30 min of intermittent tail shock during infusion of an inhibitor of aromatic amino acid decarboxylase (AAAD), NSD-1015 (100 µM), and DOPA was measured in the dialysate. Tail shock was applied beginning either 15 min after the onset of NSD-1015 treatment (the initial rate of DOPA accumulation) or 75 min after the onset of treatment (when DOPA had approached steady state). Tail shock increased the steady-state levels of extracellular DOPA in neostriatum (+40%). However, there was no change in the initial rate of DOPA accumulation unless animals also received the D₂ receptor antagonist eticlopride (50 nM), in which case an increase was observed (+228%). The impact of tail shock on the steady-state level of DOPA was attenuated by the D₂ agonist quinpirole (100 µM), or by 2-amino-5-phosphonovalerate (APV) (100 µM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (100 µM), EAA antagonists acting at NMDA or d ,l -α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) receptors, respectively. These data suggest that acute stress normally has little effect on tyrosine hydroxylation in neostriatum due to the inhibitory influence of DA in the extracellular fluid. However, when that influence is absent (e.g., during extended inhibition of DOPA decarboxylation or blockade of DA receptors), stress increases tyrosine hydroxylation via EAAs acting on NMDA and AMPA receptors. Thus, EAAs released from corticostriatal projections may stimulate DA synthesis and thereby restore dopaminergic activity under conditions in which the availability of DA for release has been compromised.     

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.     

Acute Effects of Typical and Atypical Antipsychotic Drugs on the Release of Dopamine from Prefrontal Cortex, Nucleus Accumbens, and Striatum of the Rat: An In Vivo Microdialysis Study

In vivo microdialysis has been used to study the acute effects of antipsychotic drugs on the extracellular level of dopamine from the nucleus accumbens, striatum, and prefrontal cortex of the rat. (-)-Sulpiride (20, 50, and 100 mg/kg i.v.) and haloperidol (0.1 and 0.5 mg/kg i.v.) enhanced the outflow of dopamine in the striatum and nucleus accumbens. In the medial prefrontal cortex, (-)-sulpiride at all doses tested did not significantly affect the extracellular level of dopamine. The effect of haloperidol was also attenuated in the medial prefrontal cortex; 0.1 mg/kg did not increase the outflow of dopamine and the effect of 0.5 mg/kg haloperidol was of shorter duration in the prefrontal cortex than that observed in striatum and nucleus accumbens. The atypical antipsychotic drug clozapine (5 and 10 mg/kg) increased the extracellular concentration of dopamine in all three regions. In contrast to the effects of sulpiride and haloperidol, that of clozapine in the medial prefrontal cortex was profound. These data suggest that different classes of antipsychotic drugs may have distinct effects on the release of dopamine from the nigrostriatal, mesolimbic, and mesocortical terminals.     

Differential Effect of Stress on In Vivo Dopamine Release in Striatum, Nucleus Accumbens, and Medial Frontal Cortex

Microdialysis was used to assess extracellular dopamine in striatum, nucleus accumbens, and medial frontal cortex of unanesthetized rats both under resting conditions and in response to intermittent tail-shock stress. The dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid also were measured. The resting extracellular concentration of dopamine was estimated to be approximately 10 nM in striatum, 11 nM in nucleus accumbens, and 3 nM in medial frontal cortex. In contrast, the resting extracellular levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid were in the low micromolar range. Intermittent tail-shock stress increased extracellular dopamine relative to baseline by 25% in striatum, 39% in nucleus accumbens, and 95% in medial frontal cortex. 3,4-Dihydroxyphenylacetic acid and homovanillic acid also were generally increased by stress, although there was a great deal of variability in these responses. These data provide direct in vivo evidence for the global activation of dopaminergic systems by stress and support the concept that there exist regional variations in the regulation of dopamine release.     

Receptors in the Ventral Tegmental Area Mediating Nicotine-Induced Dopamine Release in the Nucleus Accumbens

Nicotine or cocaine, when administered intravenously, induces an increase of extracellular dopamine in the nucleus accumbens. The nicotine-mediated increase was shown to occur at least in part through increase of the activity of dopamine neurons in the ventral tegmental area. As part of our continuing studies of the mechanisms of nicotine effects in the brain, in particular, effects on reward and cognitive mechanisms, in the present study we examined the role of various receptors in the ventral tegmental area in nicotine and cocaine reward. We assayed inhibition of the increase of dopamine in the nucleus accumbens induced by intravenous nicotine or cocaine administration by antagonists administered into the ventral tegmental area. Nicotine-induced increase of accumbal dopamine release was inhibited by intrategmental nicotinic (mecamylamine), muscarinic (atropine), dopaminergic (D₁: SCH 23390, D₂: eticlopride), and NMDA glutamatergic (MK 801) and GABA_B (saclofen) antagonists, but not by AMPA-kainate (CNQX, GYKI-52466) antagonists under our experimental circumstances. The intravenous cocaine-induced increase of dopamine in the nucleus accumbens was inhibited by muscarinic (atropine), dopamine 2 (eticlopride), and GABA_B (saclofen) antagonists but not by antagonists to nicotinic (mecamylamine), dopamine D₁ (SCH 23390), glutamate (MK 801), or AMPA-kainate (CNQX, GYKI-52466) receptors. Antagonists administered in the ventral tegmental area in the present study had somewhat different effects when they were previously administered intravenously. When administered intravenously atropine did not inhibit cocaine effects. The inhibition by atropine may be indirect, since this compound, when administered intrategmentally, decreased basal dopamine levels in the accumbens. The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism. Some, but not all, of these receptors in the ventral tegmental area also seem to participate in the reward mechanism of cocaine. The importance of local receptors in the ventral tegmental area was further indicated by the increase in accumbal dopamine levels after intrategmental administration of nicotine or also cocaine.     

Stress Preferentially Increases Extraneuronal Levels of Excitatory Amino Acids in the Prefrontal Cortex: Comparison to Hippocampus and Basal Ganglia

Abstract: The technique of intracerebral microdialysis was used to assess the effect of stress on the extracellular concentrations of excitatory amino acids, glutamate and aspartate, in the rat medial prefrontal cortex, hippocampus, striatum, and nucleus accumbens. A 20-min restraint procedure led to an increase in extracellular glutamate in all regions tested. The increase in glutamate levels was significantly higher in the prefrontal cortex than that observed in other regions. With the exception of the striatum, extracellular levels of aspartate were increased in all regions. Furthermore, the increase in aspartate levels was significantly higher in prefrontal cortex compared to hippocampus and nucleus accumbens. Local perfusion of tetrodotoxin during the restraint procedure significantly decreased the stress-induced increase in extracellular excitatory amino acids. In order to ensure that the above results were not an artifact of restraint not associated with stress (e.g., decreased mobility), we also examined the effect of swimming stress on the extracellular levels of excitatory amino acids in selected regions, i.e., striatum and medial prefrontal cortex. Both regions displayed a significant increase in extracellular levels of aspartate and glutamate following 20 min of swimming in room temperature water. This study provides direct evidence that stress increases the neuronal release of excitatory amino acids in a regionally selective manner. The implications of the present findings for stress-induced catecholamine release and/or hippocampal degeneration are discussed.     

Effects of Apomorphine on In Vivo Release of Dopamine and Its Metabolites in the Prefrontal Cortex and the Striatum, Studied by a Microdialysis Method

The effects of apomorphine (0.1-2.5 mg/kg) on release of endogenous dopamine and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex and the striatum were examined in vivo by a microdialysis method. Apomorphine significantly reduced release of dopamine and the extracellular levels of dopamine metabolites, DOPAC and HVA, not only in the striatum, but also in the prefrontal cortex. These findings indicate that dopamine autoreceptors modulate in vivo release of dopamine in the prefrontal cortex.     

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

Abstract: 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 ∼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 or expression of amphetamine sensitization.     

Increase of Extracellular Glutamate and Expression of Fos-Like Immunoreactivity in the Ventral Tegmental Area in Response to Electrical Stimulation of the Prefrontal Cortex

Abstract: Electrical stimulation of the medial prefrontal cortex caused glutamate release in the ventral tegmental area (VTA) of freely moving animals. Cathodal stimulation was given through monopolar electrodes in 0.1-ms pulses at an intensity of 300 µA and frequencies of 4–120 Hz. Glutamate was measured in 10-min perfusate samples by HPLC coupled with fluorescence detection following precolumn derivatization with o -phthaldialdehyde/β-mercaptoethanol. The stimulation-induced glutamate release was frequency dependent and was blocked by the infusion of the sodium channel blocker tetrodotoxin (10 µ M ) through the dialysis probe. The stimulation also induced bilateral Fos-like immunoreactivity in ventral tegmental neurons, with a significantly greater number of Fos-positive cells on the stimulated side. These findings add to a growing body of evidence suggesting that the medial prefrontal cortex regulates dopamine release in the nucleus accumbens via its projection to dopamine cell bodies in the VTA.     

BIMG 80, a Novel Potential Antipsychotic Drug: Evidence for Multireceptor Actions and Preferential Release of Dopamine in Prefrontal Cortex

Abstract: In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT_1A, 5-HT_2A, 5-HT₆), dopamine (D₁, D_2L, D₄), and noradrenergic (α₁) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.     

Fluoxetine Increases Extracellular Dopamine in the Prefrontal Cortex by a Mechanism Not Dependent on Serotonin

Fluoxetine at 10 and 25 mg/kg increased (167 and 205%, respectively) the extracellular dopamine concentration in the prefrontal cortex, whereas 25 (but not 10) mg/kg citalopram raised (216%) dialysate dopamine. No compound modified dialysate dopamine in the nucleus accumbens. The effect of 25 mg/kg of both compounds on cortical extracellular dopamine was not significantly affected by 300 mg/kg p-chlorophenylalanine (PCPA) (fluoxetine, saline, 235%; PCPA, 230%; citalopram, saline, 179%; PCPA, 181%). PCPA depleted tissue and dialysate serotonin by approximately 90 and 50%, respectively, and prevented the effect of fluoxetine and citalopram on dialysate serotonin (fluoxetine, saline, 246%; PCPA, 110%; citalopram, saline, 155%; PCPA, 96%). Citalopram significantly raised extracellular serotonin from 0.1 to 100 microM (251-520%), whereas only 10 and 100 microM increased dialysate dopamine (143-231%). Fluoxetine similarly increased extracellular serotonin (98-336%) and dopamine (117-318%). PCPA significantly reduced basal serotonin and the effects of 100 microM fluoxetine (saline, 272%; PCPA, 203%) and citalopram (saline, 345%; PCPA, 258%) on dialysate serotonin but did not modify their effect on dopamine (fluoxetine, saline, 220%; PCPA, 202%; citalopram, saline, 191%; PCPA, 211%). The results clearly show that the effects of fluoxetine and of high concentrations of citalopram on extracellular dopamine do not depend on their effects on serotonin.     

Glutamatergic Control of Dopamine Release During Stress in the Rat Prefrontal Cortex

Abstract: In vivo microdialysis was used to assess the hypothesis that the stress-induced increase in dopamine release in the prefrontal cortex is mediated by stress-activated glutamate neurotransmission in this region. Local perfusion of an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, blocked the stress-induced increase in dopamine levels, whereas an NMDA receptor antagonist, 2-amino-5-phosphonopentanoic acid, at the dose tested, was not able to alter this response significantly. These data indicate that the effect of stress on dopamine release in the prefrontal cortex is mediated locally by activation of AMPA/kainate receptors, which modulate the release of dopamine in this region.     

N-Methyl-D-Aspartate Releases Excitatory Amino Acids in Rat Corpus Striatum In Vivo

There is a considerable amount of conflicting evidence from several studies as to the action of applied N-methyl-D-aspartate (NMDA) on the release of glutamate and aspartate in the brain. In the present study the effect of NMDA on extracellular levels of endogenous amino acids was investigated in conscious, unrestrained rats using intracerebral microdialysis. NMDA caused dose-related increases in extracellular levels of glutamate and aspartate; threonine and glutamine were unaffected. The NMDA-evoked release of glutamate and aspartate was significantly decreased by the specific NMDA receptor antagonist 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-l-phosphonic acid. In addition, increasing the perfusate concentration (and therefore the extracellular concentration) of Ca2+ significantly enhanced the NMDA-evoked release of glutamate and aspartate, whereas removal of Ca2+ and addition of a high Mg2+ concentration to the perfusate caused a significant reduction in their NMDA-evoked release. Moreover, the NMDA-evoked release of glutamate and aspartate was reduced in decorticate animals. These results demonstrate that, in the striatum in vivo, NMDA causes selective release of endogenous glutamate and aspartate from neurone terminals and that this action occurs through an NMDA receptor-mediated mechanism. The ability of NMDA receptor activation to induce release of glutamate and aspartate, perhaps by a positive feedback mechanism, may be relevant to the pathologies underlying epilepsy and ischaemic and hypoglycaemic brain damage.     

Low Level Lead Exposure Decreases In Vivo Release of Dopamine in the Rat Nucleus Accumbens: A Microdialysis Study

Abstract: The basal and K⁺-induced release of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were measured in microdialysate samples obtained in vivo from the nucleus accumbens region of rats subchronically exposed to 50 ppm lead for 90 days. The basal and stimulus-induced release of dopamine and the metabolites were significantly reduced in the lead-exposed rats as compared with the controls. These reductions in dopamine and its metabolites are consistent with the reports of decreased dopamine availability associated with lead-induced changes in certain behavioral indices (fixed-interval performance) in rats. Furthermore, these changes were observed at blood lead levels similar to those considered to cause impairment in cognitive functions in children.     

Effect of Quinine on Autoreceptor-Regulated Dopamine Release in the Rat Striatum

In vivo brain microdialysis was used to examine the role of potassium channel activation in dopamine (DA) autoreceptor function in the striatum of freely moving rats. Local application of the D2 receptor agonists quinpirole or N-0437 through the dialysis probe significantly reduced extracellular concentrations of DA. Local application of the D2 antagonist (-)-sulpiride produced significant increases in DA. Local perfusion with quinine, a K+ channel blocker, completely blocked the (-)-sulpiride-induced increases in DA but did not affect the DA agonist-induced decreases. (-)-Sulpiride completely blocked the effect of quinpirole on DA both in control and in quinine-treated animals. At the highest dose used, quinine caused a large transient increase in extracellular DA. Local application of tetrodotoxin or infusion of Mg2+ in the absence of Ca2+ did not prevent this quinine-induced transient increase in extracellular DA. These results demonstrate that DA autoreceptors in the striatum regulate DA release in awake, behaving animals. Local application of (-)-sulpiride increases DA levels by blocking the tonic activation of autoreceptors by endogenous DA. Quinine blocks the neuroleptic-induced increase in DA, perhaps by preventing the K+ channel opening that would normally accompany endogenous autoreceptor activation. The fact that exogenously applied DA receptor agonists can decrease extracellular DA levels in the presence of quinine suggests that they may be acting at extrasynaptic autoreceptors that are not tonically active in vivo. The effect of DA agonists on this site is via a DA receptor because it is blocked by (-)-sulpiride. However, this receptor does not appear to be coupled to a quinine-sensitive potassium channel.     

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.