Time-of-day differences in dopamine clearance in the rat medial prefrontal cortex and nucleus accumbens

Circadian rhythms influence cocaine-seeking behavior in rats, and this behavior may be mediated by variability in the rate of extracellular dopamine clearance across the day:night cycle. We used rotating disk electrode voltammetry to examine dopamine clearance and inhibition of clearance by cocaine in the rat medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Rats were housed under light:dark conditions (LD, 12 h:12 h) or in constant darkness (DD), the latter given just prior to the day of sacrifice. Tissue was collected at 4-h intervals under LD and DD conditions. Under LD, dopamine clearance in both brain regions was greatest at 4h after lights on. Under DD, there was a blunted but still rhythmic pattern of dopamine clearance across the 24-h cycle. Cocaine-induced inhibition of dopamine clearance in the mPFC was not different across the day:night cycle in rats under LD. Paradoxically, under DD, dopamine clearance in the mPFC was enhanced by cocaine at ZT16, 4 h into the subjective night, and only minimally inhibited at other times. In the NAc, cocaine inhibition of dopamine clearance was lowest at ZT4 under LD, and did not vary under DD. We conclude that dopamine clearance varies both in a diurnal and possibly in a circadian manner in the mPFC, and in a diurnal manner in the NAc. These results indicate that light itself may be used to manipulate molecules implicated in drug addiction.     

Differential release of dopamine in the nucleus accumbens evoked by low-versus high-frequency medial prefrontal cortex stimulation

The medial prefrontal cortex (mPFC) coordinates goal-directed behaviors, which may be mediated through mPFC regulation of dopamine release in the nucleus accumbens (NAc). Furthermore, frequency-specific oscillatory activity between the frontal cortex and downstream structures may facilitate inter-region communication. Although high-frequency (e.g., 60 Hz) mPFC stimulation is known to increase basal dopamine levels in the NAc, little is known about how phasic dopamine release is affected by mPFC stimulation. Understanding the frequency-specific control of phasic dopamine release by mPFC stimulation could elucidate mechanisms by which the mPFC modulates other regions. It could also inform optimization of deep brain stimulation for treatment of neurological disorders.

Stimulation of D2 receptors in the prefrontal cortex reduces PCP-induced hyperactivity,acetylcholine release and dopamine metabolism in the nucleus accumbens

Summary. The aim of the present study was to investigate the effects of stimulation of D2 receptors in the prefrontal cortex (PFC) on spontaneous motor activity and the hyperactivity induced by the psychomimetic phencyclidine (PCP). In addition, the effects of prefrontal D2 stimulation under PCP treatment on dialysate concentrations of acetylcholine, choline, dopamine, DOPAC and HVA in the nucleus accumbens were also investigated. Sprague-Dawley male rats were implanted with guide cannulae to perform bilateral injections into the medial PFC of the D2 agonist quinpirole (1.5 and 5 μg/side). Horizontal and vertical spontaneous motor activity and the motor activity induced by systemic injections of the PCP (5 mg/kg i.p.) were monitored in the open field. PFC injections of quinpirole (1.5 and 5 μg/side) significantly decreased horizontal and vertical spontaneous motor activity in a dose-related manner. These effects were blocked by the D2 antagonist raclopride (5 μg/side). Microinjections of quinpirole (1.5 and 5 μg/side) into the PFC also significantly attenuated the hyperactivity produced by PCP (5 mg/kg i.p.). PCP also increased dialysate concentrations of acetylcholine, and dopamine metabolites in the nucleus accumbens. These increases were also reduced by injections of quinpirole (5 μg/side) into the PFC. These results suggest that the stimulation of prefrontal D2 receptors plays an inhibitory role in regulating spontaneous and PCP-induced motor activity and also in the neurochemical changes produced by PCP in the nucleus accumbens.     

Bursting activation of prefrontal cortex drives sustained up states in nucleus accumbens spiny neurons in vivo

Hippocampal inputs to the nucleus accumbens (NA) have been proposed to implement a gating mechanism by driving NA medium spiny neurons (MSNs) to depolarized up states that facilitate action potential firing in response to brief activation of the prefrontal cortex (PFC). Brief PFC stimulation alone, on the other hand, could not drive NA up states. As these studies were conducted using single‐pulse PFC stimulation, it remains possible that PFC activation with naturalistic, bursty patterns can also drive up states in NA MSNs. Here, we assessed NA responses to PFC stimulation with a pattern similar to what is typically observed in awake animals during PFC‐relevant behaviors. In vivo intracellular recordings from NA MSNs revealed that brief 20–50 Hz PFC stimulus trains evoked depolarizations that were similar to spontaneous up states in NA MSNs and were sustained beyond stimulus offset. Similar train stimulation of corticoaccumbens afferents in a parasagittal slice preparation evoked large amplitude depolarizations in NA MSNs that were sustained during stimulation but decayed rapidly following stimulation offset, suggesting that activation of cortical afferents can drive MSN depolarizations but other mechanisms may contribute to sustaining up states. These data suggest that NA MSNs integrate temporal features of PFC activation and that the NA gating model can be reformulated to include a PFC‐driven gating mechanism during periods of high PFC firing, such as during cognitively demanding tasks. Synapse 63:173–180, 2009. © 2008 Wiley‐Liss, Inc.     

Evidence for a tonic facilitatory influence of substance P on dopamine release in the nucleus accumbens

Microinjections of a monoclonal antibody substance P (SP) into the nucleus accumbens (NAS) increased the concentrations of dopamine (DA) and its metabolite 3,4-dihydroxyphenyllacetic acid (DOPAC) in the NAS but not neuroanatomically adjacent areas. SP immunoneutralization in the NAS also reduced the locomotor response to systemically administered -amphetamine. Microinjections of control antibody did not significantly alter either DA metabolism or -amphetamine-induced locomotion. These data are consistent with the hypothesis that endogenous SP modulates the release of DA in the NAS.     

Cholinergic modulation of basal and amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens

Behavioral evidence suggests that muscarinic/cholinergic inhibition of brain dopaminergic activity may be a useful principle for developing novel antipsychotic drugs (APDs). Thus, oxotremorine, a muscarinic agonist, attenuates amphetamine-induced locomotor activity in rodents, an effect also produced by a wide variety of proven APDs, whereas scopolamine, a muscarinic antagonist, has the opposite effect. Since atypical APDs such as clozapine, olanzapine, risperidone, ziprasidone and quetiapine, increase brain acetylcholine as well as dopamine (DA) release in a region-specific manner, their effects on cholinergic and dopaminergic neurotransmission may also contribute to various actions of these drugs. Oxotremorine (0.5-1.5 mg/kg) dose-dependently and preferentially increased DA release in rat medial prefrontal cortex (mPFC), compared to the nucleus accumbens (NAC). However, S-(-)-scopolamine (0.5-1.5 mg/kg) produced similar increases in DA release in the mPFC, but the effect was much less than that of oxotremorine. Whereas a dose of S-(-)-scopolamine of 0.5 mg/kg comparably increased DA release in the mPFC and NAC, 1.5 mg/kg had no effect on DA release in the NAC. Oxotremorine-M (0.5 mg/kg), a M(1/4)-preferring agonist, also increased DA release in the mPFC, but not the NAC, an effect completely abolished by telenzepine (3 mg/kg), a M(1/4)-preferring antagonist, which by itself had no effect on DA release in either region. Oxotremorine (0.5, but not 1.5, mg/kg) attenuated amphetamine (1 mg/kg)-induced DA release in the NAC, whereas S-(-)-scopolamine did not. Oxotremorine (1.5 mg/kg) and S-(-)-scopolamine (0.5 mg/kg) modestly but significantly potentiated amphetamine (1 mg/kg)-induced DA release in the mPFC. These results suggest that stimulation of muscarinic receptors, in particular M(1/4), as indicated by the effect of oxotremorine-M and telenzepine, may preferentially increase cortical DA release and inhibit amphetamine-induced DA release in the NAC.     

Projections from the paraventricular nucleus of the thalamus to the rat prefrontal cortex and nucleus accumbens shell: ultrastructural characteristics and spatial relationships with dopamine afferents

The paraventricular nucleus of the thalamus (PVT) participates in the functional integration of limbic cortical and striatal circuitry. In the rat, the PVT projects to the deep layers of the medial prefrontal cortex (PFC) and to the shell of the nucleus accumbens (NAc). However, the synaptic organization of PVT afferents within these regions remains undescribed. Furthermore, although dopamine (DA) modulates excitatory glutamate transmission in both areas, possible anatomic substrates for specific DA modulation of PVT inputs have not yet been investigated. To address these issues, immunoperoxidase labeling for tyrosine hydroxylase (TH) in DA axons was combined with anterograde tract-tracing, either by biotinylated dextran amine (BDA) labeled with immunogold-silver or by degeneration after lesions of the PVT. In both regions, and with either tracing method, PVT terminals formed primarily asymmetric axospinous synapses; in the NAc, a proportion of PVT terminals also synapsed onto dendrites. PVT profiles in both regions were often seen in direct apposition to TH-immunoreactive axons; this association was more evident in the NAc where the DA innervation is denser. Within the PFC, PVT profiles and TH-labeled axons were occasionally apposed to the same dendrites, but synaptic specializations were not typically seen at these seeming points of convergence. Within the NAc, PVT profiles occasionally made synapses onto spines and distal dendrites that received convergent synapses from TH-immunoreactive varicosities. These findings represent the first demonstration of postsynaptic convergence between DA and thalamic afferents to a striatal region and are consistent with direct synaptic modulation of PVT transmission by DA in the NAc but not the PFC.     

Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine

Depletion of cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) in adult rats increases the locomotor activating effects of amphetamine. It also impairs sensorimotor gating processes, an effect reversed by the antipsychotic haloperidol. These behavioral effects are suggestive of pronounced hyper‐responsiveness of the mesolimbic dopamine (DA) projection to the N.Acc. However, it is unclear whether local cholinergic depletion results predominantly in exaggerated presynaptic DA release or a postsynaptic upregulation of DAergic function. The purpose of the present study is to test the former possibility by employing in vivo voltammetry to examine changes in the levels of extracellular DA within the N.Acc. in response to either mild tail pinch stress or amphetamine administration. While both cholinergic‐lesioned and control rats showed reliable stress‐induced increases in extracellular DA on two consecutive test days, those in the lesioned rats were significantly less pronounced. In response to amphetamine, a separate cohort of lesioned rats also exhibited smaller increases in extracellular DA release than controls, despite showing greater locomotor activity. Moreover, the increased behavioral response to amphetamine in lesioned rats coincided temporally with decreasing levels of DA in the N.Acc. The results confirm that cholinergic depletion within the N.Acc. suppresses presynaptic DA release and suggest that lesion‐induced behavioral effects are more likely due to postsynaptic DA receptor upregulation. The results are also discussed in the context of schizophrenia, where post mortem studies have revealed a selective loss of cholinergic interneurons within the ventral striatum. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

Electrophysiological evidence for convergence of inputs from the medial prefrontal cortex and lateral habenula on single neurons in the dorsal raphe nucleus

Neuronal projections to the dorsal raphe nucleus (DRN) from the medial prefrontal cortex (mPFC) and lateral habenula nucleus (LHb) provide the two key routes by which information processed by mood regulatory, cortico-limbic-striatal circuits input into the 5-HT system. These two projections may converge as it appears that both activate local GABAergic neurons to inhibit 5-HT neurons in the DRN. Here we have tested this hypothesis by measuring the effect of stimulation of the mPFC and LHb on the activity of 5-HT and non-5-HT, putative gamma-amino butyric acid (GABA) neurons in the DRN using extracellular recordings in anaesthetized rats. A total of 119 5-HT neurons (regular, slow firing, broad spike width) and 21 non-5-HT, putative GABA neurons (fast-firing, narrow spike width) were tested. Electrical stimulation of the mPFC or LHb caused a poststimulus inhibition (30 ms latency) of 101/119 5-HT neurons, of which 61 (60%) were inhibited by both the mPFC and LHb. Electrical stimulation of the mPFC or LHb also caused a short latency (12-20 ms) poststimulus facilitation of 10/21 non-5-HT neurons, of which 5 (50%) were activated by both the mPFC and LHb. These data indicate that a significant number of 5-HT neurons and non-5-HT neurons in the DRN are influenced by both the mPFC and LHb. Moreover, the data are compatible with the hypothesis and that there is a convergence of mPFC and LHb inputs on local circuit GABAergic neurons in the DRN which in turn inhibit the activity of 5-HT neurons.     

Glutamate-dopamine in vivo interaction in the prefrontal cortex modulates the release of dopamine and acetylcholine in the nucleus accumbens of the awake rat

Summary. In the context of the in vivo neurochemical literature this article reviews some recent microdialysis studies in our laboratory of glutamate-dopamine interaction in the prefrontal cortex (PFC) and its possible role in modulating dopamine and acetylcholine release in the nucleus accumbens. A functional glutamate-dopamine interaction in PFC has been reported by microdialysis studies showing that both stimulation and blockade of prefrontal glutamate receptors produce changes of basal and/or stimulated release of dopamine in this area of the brain. These studies suggest that dopamine function in PFC is modulated locally by prefrontal glutamatergic inputs and that glutamate and dopamine can act simultaneously to regulate GABA release in PFC. In particular, dopamine can enhance the increases of extracellular GABA produced by the stimulation of prefrontal glutamate receptors. We report also that the stimulation of prefrontal D2 and mGluI receptors and their interaction changes the release of dopamine and acetylcholine in the nucleus accumbens.     

Neural correlates of Pavlovian-to-instrumental transfer in the nucleus accumbens shell are selectively potentiated following cocaine self-administration

During Pavlovian-to-instrumental transfer (PIT), learned Pavlovian cues significantly modulate ongoing instrumental actions. This phenomenon is suggested as a mechanism under which conditioned stimuli may lead to relapse in addicted populations. Following discriminative Pavlovian learning and instrumental conditioning with sucrose, one group of rats (naive) underwent electrophysiological recordings in the nucleus accumbens core and shell during a single PIT session. Other groups, following Pavlovian and instrumental conditioning, were subsequently trained to self-administer cocaine with nosepoke responses, or received yoked saline infusions and nosepoked for water rewards, and then performed PIT while electrophysiological recordings were taken in the nucleus accumbens. Behaviorally, although both naive and saline-treated groups showed increases in lever pressing during the conditioned stimulus cue, this effect was significantly enhanced in the cocaine-treated group. Neurons in the core and shell tracked these behavioral changes. In control animals, core neurons were significantly more likely to encode general information about cues, rewards and responses than those in the shell, and positively correlated with behavioral PIT performance, whereas PIT-specific encoding in the shell, but not core, tracked PIT performance. In contrast, following cocaine exposure, there was a significant increase in neural encoding of all task-relevant events that was selective to the shell. Given that cocaine exposure enhanced both behavior and shell-specific task encoding, these findings suggest that, whereas the core is important for acquiring the information about cues and response contingencies, the shell is important for using this information to guide and modulate behavior and is specifically affected following a history of cocaine self-administration.     

Role of the prefrontal cortex and nucleus accumbens in reinstating methamphetamine seeking

Although the involvement of the medial prefrontal cortex projection to the nucleus accumbens in the reinstatement of cocaine seeking has been well studied, it is not known if this projection plays a similar role in the reinstatement of cue‐ and methamphetamine‐induced drug seeking in animals extinguished from methamphetamine self‐administration. Accordingly, following extinction from long‐access methamphetamine self‐administration, rats were bilaterally microinjected with either a combination of the GABA agonists baclofen/muscimol or vehicle (artificial cerebrospinal fluid) into the infralimbic or prelimbic subcompartments of the medial prefrontal cortex or into the shell or core subcompartments of the nucleus accumbens. Similar to cocaine seeking, inactivation of either the prelimbic cortex or accumbens core eliminated cue‐ and methamphetamine‐induced reinstatement, and inactivation of neither the infralimbic cortex nor shell subcompartments inhibited methamphetamine‐induced drug seeking. However, in contrast to previous reports with cocaine, cue‐induced reinstatement of methamphetamine seeking was inhibited by inactivation of the infralimbic cortex. In conclusion, although a primary role in reinstated drug seeking by the prelimbic and the accumbens core is similar between cocaine and methamphetamine, the recruitment of the infralimbic cortex by conditioned cues differs between these two psychostimulant drugs.     

Electrophysiological evidence of mediolateral functional dichotomy in the rat nucleus accumbens during cocaine self‐administration II: phasic firing patterns

In the cocaine self‐administering rat, individual nucleus accumbens (NAcc) neurons exhibit phasic changes in firing rate within minutes and/or seconds of lever presses (i.e. slow phasic and rapid phasic changes, respectively). To determine whether neurons that demonstrate these changes during self‐administration sessions are differentially distributed in the NAcc, rats were implanted with jugular catheters and microwire arrays in different NAcc subregions (core, dorsal shell, ventromedial shell, ventrolateral shell, or rostral pole). Neural recording sessions were typically conducted on days 13–17 of cocaine self‐administration (0.77 mg/kg per 0.2‐mL infusion; fixed‐ratio 1 schedule of reinforcement; 6‐h daily sessions). Pre‐press rapid phasic firing rate changes were greater in lateral accumbal (core and ventrolateral shell) than in medial accumbal (dorsal shell and rostral pole shell) subregions. Slow phasic pattern analysis revealed that reversal latencies of neurons that exhibited change + reversal patterns differed mediolaterally: medial NAcc neurons exhibited more early reversals and fewer progressive/late reversals than lateral NAcc neurons. Comparisons of firing patterns within individual neurons across time bases indicated that lateral NAcc pre‐press rapid phasic increases were correlated with tonic increases. Tonic decreases were correlated with slow phasic patterns in individual medial NAcc neurons, indicative of greater pharmacological sensitivity of neurons in this region. On the other hand, the bias of the lateral NAcc towards increased pre‐press rapid phasic activity, coupled with a greater prevalence of tonic increase firing, may reflect particular sensitivity of these neurons to excitatory afferent signaling and perhaps differential pharmacological influences on firing rates between regions.     

Reward-guided learning beyond dopamine in the nucleus accumbens: the integrative functions of cortico-basal ganglia networks

Here we challenge the view that reward-guided learning is solely controlled by the mesoaccumbens pathway arising from dopaminergic neurons in the ventral tegmental area and projecting to the nucleus accumbens. This widely accepted view assumes that reward is a monolithic concept, but recent work has suggested otherwise. It now appears that, in reward-guided learning, the functions of ventral and dorsal striata, and the cortico-basal ganglia circuitry associated with them, can be dissociated. Whereas the nucleus accumbens is necessary for the acquisition and expression of certain appetitive Pavlovian responses and contributes to the motivational control of instrumental performance, the dorsal striatum is necessary for the acquisition and expression of instrumental actions. Such findings suggest the existence of multiple independent yet interacting functional systems that are implemented in iterating and hierarchically organized cortico-basal ganglia networks engaged in appetitive behaviors ranging from Pavlovian approach responses to goal-directed instrumental actions controlled by action-outcome contingencies.     

Differential effect of cocaine on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens: comparison to amphetamine

The technique of in vivo microdialysis was used to measure the extracellular levels of dopamine in the nucleus accumbens septi and medial prefrontal cortex of chloral-hydrate-anaesthetized rats following systemic administration of cocaine and amphetamine. Intravenous injection of cocaine increased the extracellular levels of dopamine in the medial prefrontal cortex and the nucleus accumbens septi in a dose-dependent manner. However, the magnitude of increase was significantly greater in nucleus accumbens than in medial prefrontal cortex. In comparison to cocaine, amphetamine increased the extracellular levels of dopamine in the nucleus accumbens and medial prefrontal cortex to the same degree. Based on the relatively small increase of extracellular dopamine levels in medial prefrontal cortex by cocaine, it is postulated that dopaminergic innervation of other structures besides medial prefrontal cortex may be involved in maintenance of cocaine self-administration.     

Chronic phencyclidine treatment increases dendritic spine density in prefrontal cortex and nucleus accumbens neurons

We examined whether repeated exposure to the noncompetitive NMDA receptor antagonist phencyclidine (PCP) produces enduring changes in dendritic structure in a manner similar to the stimulants cocaine and amphetamine. Adult rats were treated with i.p. injections of PCP (5 mg/kg) or saline, twice a day, for 5 consecutive days, for a total of 4 weeks. One month after the last injection, their brains were removed and processed for Golgi-Cox staining. Prior exposure to PCP increased dendritic spine density in the mPFC and NAcc core, but not in the parietal cortex. These findings, which are similar to those observed after chronic treatment with cocaine and amphetamine, raise the possibility that, despite differences in their mechanisms of action, PCP and stimulant drugs may induce some of their enduring effects via common processes.     

Ratio and time requirements on operant schedules: effort-related effects of nucleus accumbens dopamine depletions

Accumbens dopamine (DA) depletions produce deficits that are related to the ratio requirement of the operant schedule; however, it is also possible that time without reinforcement is a factor. The present study examined the effects of accumbens DA depletions in rats using variable interval (VI) schedules with additional fixed ratio (FR) requirements. Four VI schedules were used (VI 60/FR 1, VI 120/FR 1, VI 60/FR 10, VI 120/FR 10). Attachment of the additional work requirement increased response rates under control conditions. After surgery, there was no interaction between interval level (i.e. 60 vs. 120 s) and DA depletion, but there was a significant interaction between ratio requirement (i.e. 1 vs. 10) and DA depletion within the first week after surgery. DA depletions substantially impaired performance on the schedules with added FR 10 requirements, an effect that was largely dependent upon a reduction in fast responses (i.e. inter-response times less than 1.0 s). There was little effect of DA depletion on overall responding on VI 60/FR 1 and VI 120/FR 1 schedules. DA depletions also increased the tendency to take long pauses in responding (i.e. > 20.0 s), and this effect was evident across all schedules tested. Thus, accumbens DA depletions interact with work requirements and blunt the rate-enhancing effects of moderate size ratios, and also enhance the tendency to pause. Attachment of ratio requirements to interval schedules is a work-related response cost that provides a challenge to the organism, and DA in nucleus accumbens appears to be necessary for adapting to this challenge.     

The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently from peripheral sources. Clinical studies in humans have associated these hormones with depression and postpartum mood disorders. In rodents, allopregnanolone (AlloP) has been shown to have anxiolytic and rewarding properties. These observations suggest that neurosteroids could interact with mood and motivation. However, the possible neural substrates of these effects remain unknown. In this report, we have studied the action of AlloP on the activity of the mesencephalic dopaminergic (DA) projection to the nucleus accumbens, which is considered one of the biological substrates of motivation and reward. This study was conducted by measuring extracellular concentrations of dopamine (DA) in the nucleus accumbens by means of microdialysis in freely moving rats. We studied both the direct effect of AlloP and the influence of this hormone on the DA response to an injection of morphine. AlloP dose-dependently increased the release of DA in the nucleus accumbens. Furthermore, this hormone doubled the DA response to morphine. These effects were observed for AlloP doses of 50 and 100 pmol injected intracerebroventricularly. These results suggest that the stimulatory effect of AlloP on DA could mediate some of the behavioural effects of neurosteroids and, in particular, the interaction of these hormones with mood and motivation.     

Conditioned appetitive stimulus increases extracellular dopamine in the nucleus accumbens of the rat

This study used in vivo microdialysis to examine the release of dopamine (DA) in the nucleus accumbens (nAc) during the performance of a previously learned, signalled sucrose reward task, and during conditioning of a neutral tone stimulus to this reward. Behavioural measures (magazine entries) confirmed that stimuli associated with sucrose presentation became secondary rewarding stimuli, and DA release was also monitored during subsequent presentation of these stimuli alone. Perhaps surprisingly, during magazine entry for consumption of sucrose, i.e. in conditions similar to routine training, dialysate DA levels in the nAc did not increase. In contrast, during conditioning of the tone with light-sucrose, dopamine levels increased consistently and significantly. Interestingly, DA levels were somewhat, but significantly, increased when tone alone was presented in a test session, i.e. two hours after conditioning, and even more so when tone was combined with the light previously associated with sucrose. In this latter case the number of magazine entries increased to a level similar to that seen during conditioning. Presentation of light alone resulted in a similar level of magazine entries to tone alone, but no significant increase in DA. In summary, these studies confirm that a neutral stimulus can acquire the behavioural properties of reward when conditioned. The neurochemical data, on the other hand, suggest that increases of DA in nAc are more likely to be related to new associative learning than to established incentive or consumatory processes. The increase in DA release in the test session may be related either to the secondary reinforcing properties acquired by the stimulus, or to the change in contingencies, or to the aversive effects of the omission of reward.     

Interactions of cholecystokinin octapeptide and dopamine on nucleus accumbens neurons

Local microiontophoretic administration of cholecystokinin octapeptide (CCK) increased the firing rates of neurons in the dorsomedial nucleus accumbens (NAc), but exerted little to no effect on lateral NAc neurons. This regionally defined CCK-effect corresponds to the topographical distribution of CCK-like immunoreactive nerve terminal fiber networks and CCK receptors within the NAc. The excitatory effects of CCK were selectively antagonized by the CCK antagonist proglumide. Dopamine (DA) decreased the firing of NAc cells and reversed CCK-induced excitation. These results suggest that CCK and DA may interact to influence the activity of neurons within the dorsomedial NAc.