The abused inhalant toluene increases dopamine release in the nucleus accumbens by directly stimulating ventral tegmental area neurons.

Recreational abuse of toluene-containing volatile inhalants by adolescents is a significant public health problem. The mechanisms underlying the abuse potential of such substances remain unclear, but could involve increased activity in mesoaccumbal dopamine (DA) afferents innervating the nucleus accumbens (ACB). Here, using in vitro electrophysiology, we show that application of behaviorally relevant concentrations of toluene directly stimulates DA neurons in the ventral tegmental area (VTA), but not surrounding midbrain regions. Toluene stimulation of VTA neurons persists when synaptic transmission is reduced. Moreover, unlike non-DA neurons, the magnitude of VTA DA neuron firing does not decline during longer exposures designed to emulate 'huffing'. Using dual-probe in vivo microdialysis, we show that perfusion of toluene directly into the VTA increases DA concentrations in the VTA (somatodendritic release) and its terminal projection site, the ACB. These results provide the first demonstration that even brief exposure to toluene increases action potential drive onto mesoaccumbal VTA DA neurons, thereby enhancing DA release in the ACB. The finding that toluene stimulates mesoaccumbal neurotransmission by activating VTA DA neurons directly (independently of transynaptic inputs) provide insights into the neural substrates that may contribute to the initiation and pathophysiology of toluene abuse.     

Morphine-dopamine interaction: ventral tegmental morphine increases nucleus accumbens dopamine release

Microdialysis and high-performance liquid chromatography with electrochemical detection were used to determine extracellular levels of dopamine following ventral tegmental morphine injections into chloral hydrate-anesthetized rats. Morphine (13.2 nanomoles in 0.5 microliter of Ringer's solution) caused 50-150% increases in nucleus accumbens dopamine and metabolites; latency for the effect was on the order of 15 min with peak effects occurring in 30-50 min. Contralateral dopamine levels were influenced only minimally. These data suggest opiate receptors in or near the ventral tegmental area as sites of the opioid action that is responsible for opioid activation of the mesolimbic dopamine system.     

Activation of 5-HT(1B/1D) receptors in the mesolimbic dopamine system increases dopamine release from the nucleus accumbens: a microdialysis study

This study was designed to investigate the role of 5-hydroxytryptamine (5-HT)(1B) receptors located in the ventral tegmental area and nucleus accumbens in the modulation of accumbal dopaminergic transmission. The selective 5-HT(1B) receptor agonist CP 93129 [3-(1,2,5,6-tetrahydro-4-pyridyl)pyrrolo[3,2-b]pyrid-5-one] was administered into the ventral tegmental area or nucleus accumbens of freely moving Sprague-Dawley rats via retrograde microdialysis. The effects of intra-accumbal and intra-tegmental CP 93129 on extracellular dopamine levels in the nucleus accumbens were measured using one- and dual-probe microdialysis, respectively. For dual-probe microdialysis, one probe was in the ventral tegmental area for drug administration and the other in the ipsilateral nucleus accumbens for dopamine measurement. The results show that infusion of CP 93129 (2, 5 and 10 microM) into the nucleus accumbens increased local dopamine levels in a concentration-related manner. Infusion of CP 93129 (10 and 20 microM) into the ventral tegmental area also increased dopamine levels in the ipsilateral nucleus accumbens. The increased dopamine release in the nucleus accumbens produced by intra-accumbal or intra-tegmental CP 93129 was antagonized by co-infusion of cyanopindolol (5 microM), a 5-HT(1B/1A) receptor antagonist, but not by WAY-100635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridinyl-cyclohexanecarboxamide] (5 microM), a highly selective 5-HT(1A) receptor antagonist. In addition, augmentations of dopamine release in the nucleus accumbens induced by intra-accumbal CP 93129 were sensitive to Na(+) channel blockade with tetrodotoxin. These results are not in opposition to the concept that 5-HT(1B) receptors within the ventral tegmental area and nucleus accumbens are all involved in the modulation of dopamine release in the terminal area of the mesolimbic dopamine system.     

Acetaldehyde increases dopaminergic neuronal activity in the VTA.

Acetaldehyde is the first and principal metabolite of ethanol administered systemically. To its rise in blood, after administration of disulfiram, is ascribed the aversive reaction that should discourage alcoholics from drinking. In the present study, we sought to determine the effect of acetaldehyde on the electrophysiological properties of dopamine (DA)-containing neurons in the ventro tegmental area (VTA) of rats in vivo. Intravenous (i.v.) administration of acetaldehyde (5-40 mg/kg) readily and dose-dependently increased the firing rate, spikes/burst, and burst firing of VTA neurons. Ethanol (250-1000 mg/kg/i.v.) administration produced similar increments in electrophysiological parameters. In addition, a second group of rats was pretreated with the alcohol-dehydrogenase inhibitor 4-methyl-pyrazole (90 mg/kg) intraperitoneally (i.p.), and ethanol and acetaldehyde were administered i.v. at the same doses, 48 h later. In this group, ethanol effects were drastically reduced and the firing rate, spikes/burst, and burst firing were not significantly altered. In contrast, acetaldehyde fully retained its capacity to stimulate electrophysiological indices. The results indicate that acetaldehyde produces electrophysiological actions on VTA neurons in vivo, similar to those produced by ethanol, and significantly participate in ethanol-induced increment in DA neuronal activity. These results also suggest that acetaldehyde, by increasing DA neuronal activity in the VTA, may significantly contribute to the centrally mediated positive motivational properties of ethanol, which would oppose the well-known peripherally originating aversive properties.     

Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens

BACKGROUND AND PURPOSE

Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline''s effects on ethanol consumption.

EXPERIMENTAL APPROACH

Rats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV).

KEY RESULTS

Microinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc.

CONCLUSION AND IMPLICATIONS

Following long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline''s effects on ethanol consumption.     

GABAergic blockade of cocaine-associated cue-induced increases in nucleus accumbens dopamine

Environments previously associated with drug use can become one of the most common factors triggering relapse to drug-seeking behavior. To better understand the neurochemical mechanisms potentially mediating these cues, we measured nucleus accumbens dopamine levels in animals exposed to environmental cues previously paired with cocaine administration. In animals exposed to a cocaine-paired environment nucleus accumbens dopamine increased by 25%. When administered 2.5 h prior to presentation of the environmental trigger, racemic vigabatrin (an irreversible inhibitor of gamma-aminobutyric acid (GABA)-transaminase) abolished this cue-induced increase. Conversely, R-(-)-vigabatrin, the inactive enantiomer, had no effect. Combined with our earlier findings, these studies support the potential therapeutic benefit of this enzyme-based GABAergic strategy to modulate brain dopamine and the subsequent treatment of drug addiction.     

Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum

The in vivo effects of olanzapine on the extracellular monoamine levels in rat prefrontal cortex (Pfc), nucleus accumbens (Acb) and striatum (Cpu) were investigated by means of microdialysis. Sequential doses of olanzapine at 0.5, 3 and 10 mg/kg (SC) dose-dependently increased the extracellular dopamine (DA) and norepinephrine (NE) levels in all three brain areas. The increases appeared 30 min after olanzapine administration, reached peaks around 60–90 min and lasted for at least 2 h. The highest DA increases in the Acb and Cpu were induced by olanzapine at 3 mg/kg but at 10 mg/kg in the Pfc. The peak DA increase in the Pfc (421% ± 46 of the baseline) was significantly larger than those in the Acb (287% ± 24) and Cpu (278% ± 28). Similarly, the highest NE increase in the Pfc (414%±40) induced by 10 mg/kg olanzapine was larger than those in the Acb (233% ± 39) and Cpu (223% ± 24). The DA and NE increases in the Pfc induced by olanzapine at 3 and 10 mg/kg (SC) were slightly larger than those induced by clozapine at the same doses. In contrast, haloperidol (0.5 and 2 mg/kg, SC) did not change Pfc DA and NE levels. Extracellular levels of a DA metabolite, DOPAC, and tissue concentrations of a released DA metabolite, 3-methoxytyramine, were also increased by olanzapine, consistent with enhanced DA release. However, olanzapine at the three sequential doses did not alter the extracellular levels of either 5-HT or its metabolite, 5-HIAA, in any of the three brain areas. In conclusion, the present studies demonstrate that in the case of sequential dosing olanzapine more effectively enhances DA and NE release in the Pfc than in the subcortical areas, which may have an impact on its atypical antipsychotic actions. Received: 7 May 1997/Final version: 15 September 1997     

Repetitive transcranial magnetic stimulation increases the release of dopamine in the nucleus accumbens shell of morphine-sensitized rats during abstinence.

Recent studies in rodents have shown that withdrawal from chronic drug abuse is associated with a significant decrease in dopamine (DA) release in mesolimbic structures, especially in the shell region of the nucleus accumbens. Since the DA system is known to play an important role in reward processes, a withdrawal-associated impairment in mesolimbic DA-mediated transmission could possibly implicate reward deficit and thus enhance vulnerability to drug craving and relapse. We have previously demonstrated that acute repetitive transcranial magnetic stimulation (rTMS) has a modulatory effect on DA release in several areas of the rat brain, including dorsal striatum, hippocampus, and nucleus accumbens shell. In the present study, we investigated the possible use of rTMS as a tool in re-establishing the dysregulated DA secretion observed during withdrawal in morphine-sensitized male Sprague-Dawley rats. Using intracerebral microdialysis, we monitored the effects of acute rTMS (20 Hz) on the intra-accumbal release-patterns of DA in freely moving animals that were subjected to a morphine sensitization scheme for a period of 8 days. We provide first evidence that acute rTMS (20 Hz) is able to increase DA concentration in the shell region of the nucleus accumbens in both control animals and morphine-sensitized rats during abstinence. The DA release in morphine-sensitized rats was significantly higher than in controls. rTMS, therefore, might gain a potential therapeutic role in the treatment of dysphoric and anhedonic states during drug withdrawal in humans.     

Cholinergic action in the nucleus accumbens: modulation of dopamine and acetylcholine release.

The action of oxotremorine and acetylcholine on the release of dopamine and acetylcholine from tissue slices of the rat nucleus accumbens was studied. Oxotremorine significantly enhanced the release of [14C]-dopamine evoked by 34 mMK+ and the EC50 for this action was 1.5 X 10(-7)M. A maximal enhancement (30%) for this effect was reached at 2 X 10(-7)M oxotremorine. A further enhancement of dopamine release occurred at concentrations of oxotremorine greater than 10(-4)M. The action of oxotremorine on [14C]-dopamine release was calcium-dependent and blocked by atropine (10(-4) M) but not mecamylamine (up to 10(-4) M). Oxotremorine affected [3H]-acetylcholine release differentially, inhibiting the K+-evoked release of [3H]-acetylcholine at concentrations greater than 10(-5) M. The IC50 for this process was 4.3 X 10(-5) M. Acetylcholine (8 X 10(-4) M) showed a similar pattern of action to oxotremorine: it enhanced the K+-evoked release of [14C]-dopamine (50%) and inhibited the K+-evoked release of [3H]-acetylcholine (30%). The mechanism of action of oxotremorine on dopamine release is discussed in terms of a presynaptic receptor-mediated process.     

Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens

The extent to which repeated administration produces tolerance to nicotine-induced increases in dopamine transmission in the nucleus accumbens was investigated in rats. In vivo microdialysis was used to sample extracellular dopamine and metabolites after a nicotine challenge (0.35 mg/kg) in (1) naive rats, (2) acutely pretreated rats (1 prior nicotine injection), and (3) chronically pretreated rats (12-15 prior daily nicotine injections, 0.35 mg/kg per injection). Nicotine increased extracellular DA and its metabolites, and these increases were not significantly altered by either acute or chronic prior exposure to the drug. The failure to find evidence of tolerance is compatible with the hypothesis that the mesolimbic dopaminergic system is a substrate for the reinforcing properties of chronically administered nicotine.     

Pentylenetetrazol-kindling modulates stimulated dopamine release in the nucleus accumbens of rats

Kindling-induced activation of dopaminergic neurones in the nucleus accumbens in pentylenetetrazol (PTZ)-kindled rats was studied using microdialysis. Dopamine (DA) release after PTZ challenge was measured: (1) two weeks and (2) ten weeks after kindling completion and (3) two weeks after a kindling procedure with diazepam (DZP) treatment. In (1) a significant increase in DA concentration was found after PTZ challenge and this increase was still evident 10 weeks after kindling completion (2). Coadministration of DZP in the course of kindling development inhibited the increase in sensitivity of the accumbens dopaminergic system (3).     

Cocaine increases 5-HT1B mRNA in rat nucleus accumbens shell neurons

Serotonin 5-HT(1B) receptors modulate behavioral responses to cocaine, but the effects of cocaine on endogenous 5-HT(1B) receptor expression are not known. Therefore, we examined the effect of binge cocaine administration on 5-HT1B mRNA expression in rat brain. We found that chronic, but not acute, binge cocaine exposure increased 5-HT(1B) mRNA by approximately 80% in nucleus accumbens shell and dorsal striatum. Surprisingly, 5-HT(1B) mRNA was increased in nucleus accumbens shell after chronic vehicle treatment as well, but this effect was driven by animals that were housed with cocaine-treated animals. Thus, 5-HT(1B) mRNA is upregulated by repeated exposure to cocaine and perhaps by social stress as well; both of these factors are relevant to the risk for relapse in cocaine addiction.     

Blockade of NMDA receptors in the prefrontal cortex increases dopamine and acetylcholine release in the nucleus accumbens and motor activity

Objectives  The present study investigates the effects of injections of a specific N-methyl-d-aspartic acid (NMDA) antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) into the prefrontal cortex (PFC) on the extracellular concentrations of dopamine and acetylcholine in the nucleus accumbens (NAc) and on motor activity in the freely moving rat. Materials and methods  Sprague–Dawley male rats were implanted with guide cannulas into the medial PFC and NAc to perform bilateral microinjections and microdialysis experiments. Spontaneous motor activity was monitored in the open field. Results  Injections of CPP (1 μg/0.5 μL) into the PFC produced a significant increase of the baseline extracellular concentrations of dopamine (up to 130%), dihydroxyphenylacetic acid (DOPAC; up to 120%), homovanillic acid (HVA; up to 130%), and acetylcholine (up to 190%) in the NAc as well as motor hyperactivity. In the NAc, perfusion of the NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate antagonists CPP (50 μM)+6,7-dinitroquinoxaline-2,3-dione (DNQX; 50 μM) through the microdialysis probe blocked acetylcholine release, but not DOPAC and HVA increases produced by CPP injections into the PFC. Also, increases in motor activity produced by prefrontal injections of CPP were significantly reduced by bilateral injections into the NAc of a mixed D1/D2 antagonist, flupenthixol (5 and 25 μg/0.5 μL). Injections into the NAc of the muscarinic antagonist scopolamine (1 and 10 μg/0.5 μL) further increased, and of the nicotinic antagonist mecamylamine (1 and 10 μg/0.5 μL) did not change, the increases in motor activity produced by prefrontal CPP injections. Conclusions  These results suggest that the dysfunction of NMDA receptors in the PFC could be a key factor in the neurochemical and motor effects associated with corticolimbic hyperactivity.     

Acute beta-amyloid administration disrupts the cholinergic control of dopamine release in the nucleus accumbens.

The clinical presentation of Alzheimer's disease is characterized by memory deficits but it also involves the impairment of several cognitive functions. Some of these cognitive and executive functions are mediated by limbic areas and are regulated by dopaminergic neurotransmission. Furthermore, literature data suggest that beta-amyloid (Abeta) can influence synaptic activity in absence of neurotoxicity and in particular can impair cholinergic modulation of other neurotransmitter actions. In the present study, we evaluated whether small concentrations of Abeta could disrupt cholinergic control of dopamine (DA) release in nucleus accumbens using in vivo (brain dialysis) and in vitro (isolated synaptosomes) models. The cholinergic agonist carbachol (CCh) greatly enhanced DA release from dopaminergic nerve endings in nucleus accumbens both in vivo and in vitro. This effect was mainly exerted on muscarinic receptors because it was inhibited by the muscarinic antagonist atropine and it was unaffected by the nicotinic antagonist mecamylamine. Also the nicotinic agonists epibatidine and nicotine evoked a dopaminergic outflow in nucleus accumbens, which, however, was lower. Abeta 1-40 in absence of neurotoxicity fully inhibited the DA release evoked by CCh and only marginally affected the DA release evoked by epibatidine. The PKC inhibitor GF109203X mimicked the effect of Abeta on DA release and, in turn, Abeta impaired PKC activation by CCh. We can suggest that, in nucleus accumbens, Abeta disrupted in vivo and in vitro cholinergic control of DA release by acting on muscarinic transduction machinery.     

Activation of the retrohippocampal region in the rat causes dopamine release in the nucleus accumbens: disruption by fornix section

There is a well-described projection from the retrohippocampus (subiculum and entorhinal cortex) to the nucleus accumbens that is involved in the control of psychomotor behaviour, and is implicated in the aetiology of schizophrenia. Cortical abnormalities are widely reported in the brains of schizophrenic patients, but it is unclear whether they are the cause or consequence of those changes in subcortical systems that are treated with neuroleptic drugs. We have, therefore, conducted a series of microdialysis experiments in anaesthetized rats to determine whether infusion of the excitotoxin, N-methyl-D-aspartate, into the retrohippocampus increases mesolimbic dopamine release. We found a clear and reproducible increase in extracellular dopamine in the nucleus accumbens following N-methyl-D-aspartate (2.5 microg), that was abolished when we sectioned the fimbria-fornix. Furthermore, inhibition of gamma-aminobutyric acid receptors following retrohippocampus administration of bicuculline (4 microg), also increased dopamine in the nucleus accumbens. The dopamine response to bicuculline was accompanied by an increase in dopamine metabolism, was long lasting, and also reduced by fornix section.The response to both N-methyl-D-aspartate and bicuculline depends on the integrity of the projection from the retrohippocampus to the nucleus accumbens. The results provide an underlying mechanism whereby a primary insult in the temporal cortex, caused by excessive N-methyl-D-aspartate receptor stimulation, can produce a hyperdopaminergic state. In addition, an increase in subiculo-accumbens activity evoked by bicuculline may also explain why patients with limbic epilepsy can develop a psychosis.     

Tianeptine increases the extracellular concentrations of dopamine in the nucleus accumbens by a serotonin-independent mechanism.

The effect of various doses of tianeptine on the extracellular concentrations of dopamine was studied in the striatum and nucleus accumbens of the rat. At 5 (but not 2.5) mg/kg intraperitoneally, tianeptine increased the extracellular dopamine only in the nucleus accumbens. At 10 mg/kg, the effect was also seen in the striatum but it was less marked and shorter-lasting. At 10 mg/kg (i.p.), tianeptine significantly raised the extracellular concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in both regions. The effect of 10 mg/kg tianeptine on dopamine and its metabolites was not significantly changed in animals which had received this dose twice daily for 15 days. Intracerebroventricular administration of 150 micrograms/20 microliters 5,7-dihydroxytryptamine, which markedly depleted serotonin in the brain, did not modify the effect of 10 mg/kg tianeptine on the extracellular concentrations of dopamine and HVA in the nucleus accumbens but reduced the effect on DOPAC. Various doses of tianeptine (1, 3 and 10 mg/kg i.p.) did not change the synthesis of serotonin and dopamine in the striatum and nucleus accumbens. The results show that tianeptine increased the extracellular concentrations of dopamine more in the nucleus accumbens than in striatum. The effect on the output of DA in the nucleus accumbens could be involved in the antidepressant activity of tianeptine.     

Electroconvulsive shock increases dopamine D1 and D2 receptor mRNA in the nucleus accumbens of the rat

The present study examined the effects of acute and repeated administration of electroconvulsive shock (ECS) on levels of D₁ and D₂ receptor mRNAs in the nucleus accumbens and striatum (caudate-putamen) of the rat. Quantitative in situ hybridisation with³⁵S-labelled oligonucleotide probes specific for D₁ and D₂ receptor mRNAs was utilised. Compared to controls, rats receiving a single ECS showed higher levels of both D₁ and D₂ receptor mRNAs in the nucleus accumbens 4 h, but not 24 h, after treatment. Similarly, rats receiving ECS repeatedly (five ECS in 10 days) also exhibited higher levels of D₁ and D₂ receptor mRNAs in the nucleus accumbens 4 h, but not 24 h, after the last treatment. The effects of single and repeated ECS treatment on dopamine receptor mRNA levels were localised to the caudal region of the nucleus accumbens. No statistically significant changes in mRNA levels were detected in the striatum of rats treated with either acute or repeated ECS. We discuss the possibility that increased expression of D₁ and D₂ receptors in the nucleus accumbens may be involved in the dopamine-enhancing properties of ECS detected in behavioural studies.     

Chronic desipramine enhances amphetamine-induced increases in interstitial concentrations of dopamine in the nucleus accumbens

There is accumulating evidence that some antidepressant treatments can increase the functional output of the meso-accumbens dopaminergic system. For example, chronic administration of tricyclic antidepressant drugs such as imipramine and desipramine (DMI) enhances the locomotor stimulant effects of d-amphetamine. Subsensitivity of inhibitory dopamine (DA) autoreceptors and supersensitivity of postsynaptic DA receptor mechanisms are among the mechanisms that have been suggested to underlie these observations. The present experiments investigated the effects of acute and chronic DMI treatment on interstitial DA concentrations in the nucleus accumbens and striatum using in vivo microdialysis in awake freely moving rats (48 h following implantation of a microdialysis probe). Neither acute (5 mg/kg b.i.d. for 2 days followed by 72 h withdrawal) nor chronic (5 mg/kg b.i.d. for 21 days followed by 72 h withdrawal) DMI influenced the ability of apomorphine (25 micrograms/kg s.c.) to decrease extracellular concentrations of DA or its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens. In contrast, d-amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the nucleus accumbens of the chronic but not the acute DMI group. This effect was at least partially regionally selective, as significant effects were not observed in the striatum. In accordance with previous reports, the locomotor stimulant effects of d-amphetamine were also enhanced in the chronic DMI groups. DMI itself failed to alter the interstitial concentrations of DA and its metabolites in the nucleus accumbens of the control and chronic DMI groups. These results provide in vivo neurochemical confirmation that chronically administered DMI does not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a selective potentiation of the effects of this stimulant on interstitial DA concentrations in the nucleus accumbens.     

Characterization of cholecystokinin octapeptide-stimulated endogenous dopamine release from rat nucleus accumbens in vitro.

1. The effect of cholecystokinin sulphated octapeptide (CCK8S) on endogenous dopamine release was examined in rat striatal and nucleus accumbens slices, by high performance liquid chromatography (h.p.l.c.) with electrochemical detection. 2. CCK8S was shown to increase dopamine release from slices of nucleus accumbens but not striatum in a dose-dependent manner between 0.1 and 10 microM. 3. Pentagastrin was without effect on dopamine release at doses up to 10 microM. 4. The dopamine release produced in the presence of CCK8S was abolished by preincubation of the slice with 1.0 or 10.0 nM L-364,718 (the CCKA-selective antagonist) while 1 microM L-365,260 (the CCKB-selective antagonist) had no action. 5. These results suggest that the CCK8S-evoked release of dopamine from the nucleus accumbens is mediated by a CCKA-receptor.