Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin

The effect of intracerebral injections of 5,7-dihydroxy-tryptamine (5,7-DHT) on cocaine self-administration behavior was assessed. Rats were tested on a progressive ratio (PR) schedule for cocaine reinforcement. The first response on the lever each day produced an IV infusion of cocaine (0.6 mg/injection) after which the requirements of the schedule escalated with each reinforcement until the behavior extinguished. The final ratio completed was defined as the breaking point. Bilateral injections of 5,7-DHT into either the medial forebrain bundle (MFB) or amygdala (AMY) significantly increased the breaking points on the PR schedule compared to vehicle-injected control animals. We interpret these data to indicate that depletion of forebrain serotonin increases the incentive value of cocaine.     

Lack of an effect of 6-hydroxydopamine lesions of the nucleus accumbens on intravenous morphine self-administration

The neurotoxin, 6-hydroxydopamine (6-OHDA), has been used to selectively destroy dopamine containing neurons in discrete brain regions. Lesions of the nucleus accumbens with this neurotoxin decrease or eliminate cocaine and amphetamine self-administration and either increase or do not affect opiate self-administration in rats with unrestricted access to food and water. This study reports the effects of 6-OHDA lesions of the nucleus accumbens on responding maintained by food, water or morphine (3.3 mg/infusion). Six male rats with continuous access to three response levers were trained on a concurrent chained, fixed-ratio 1, fixed-ratio 9 schedule of reinforcer presentation. After stable patterns of responding were maintained by the three reinforcers, dose-effect curves for morphine were determined by substituting other doses of morphine or vehicle for 24-hour periods. Bilateral sham vehicle or 6-OHDA lesions of the nucleus accumbens were then completed and the effects of the lesion on food, water and morphine intake determined. Dose-effect evaluations were repeated after the lesion. The 6-OHDA lesions did not significantly affect responding maintained by food, water or morphine. The absence of an effect is most likely not the result of an insensitive baseline since other neurotoxin lesions produce long-term and selective decrements in morphine self-administration without affecting food and water responding. Like so many other manipulations, the magnitude of the effect that a neurotoxin lesion can exert on behavior may depend on the specific procedures that are used to maintain responding.     

Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens

The effect of 6-OHDA injections into the nucleus accumbens was examined on cocaine self-administration behaviour. Rats were given access to cocaine (0.75 mg/kg/inj.) for three hours/day on a continuous reinforcement schedule. After daily intake of cocaine had stabilized, rats were injected with 6-OHDA (8 μg/2 μl). When tested the day following the 6-OHDA injection most rats failed to self-administer cocaine, however this disruption did not resemble extinction. After several days self-administration recovered in many animals to near preoperative levels, and the rate of this recovery correlated (r = +0.75) with the levels of dopamine remaining in the nucleus accumbens. The animals with the greatest depletion of dopamine did not recover cocaine intake. In a separate experiment, animals were pretreated with desmethylimipramine and/or pargyline to achieve a more extensive and selective lesion. When tested five days after the lesion all animals in these 6-OHDA groups showed a significant decline in cocaine intake compared to vehicle injected control animals. Several 6-OHDA treated animals displayed a pattern of behaviour resembling extinction, where a high rate of lever pressing was followed by cessation of responding. Some animals were aalso tested for apomorphine self-administration and this was found not to be affected by the 6-OHDA treatment. These data support the hypothesis that non-striatal dopamine may subserve cocaine reward.     

The response of apomorphine administered into the accumbens in rats with bilateral lesions of the nucleus accumbens, induced with 6-hydroxydopamine

Bilateral lesions of the nucleus accumbens, induced with 6-hydroxydopamine, reduced motor activity and produced a 20-35% depletion of the concentrations of dopamine (DA) and its main metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Small doses of apomorphine (1-10 ng), injected into the nucleus accumbens of sham-lesioned rats, decreased motor activity, while larger doses (1-10 micrograms) produced hyperactivity. In rats lesioned with 6-hydroxydopamine, apomorphine caused hyperactivity only, and this apomorphine-induced response was more pronounced than in sham-lesioned rats. Large doses of apomorphine decreased, only in sham-lesioned animals, the levels of DOPAC and HVA. These data suggest that the apomorphine-induced hypomotility is mediated by presynaptically located DA receptor systems in the nucleus accumbens, whereas the apomorphine-induced hypermotility is likely to be mediated by postsynaptically located DA receptor systems.     

Effect of quinolinic acid-induced lesions of the nucleus accumbens core on performance on a progressive ratio schedule of reinforcement: implications for inter-temporal choice

Rationale The nucleus accumbens core (AcbC) is believed to contribute to the control of operant behaviour by reinforcers. Recent evidence suggests that it is not crucial for determining the incentive value of immediately available reinforcers, but is important for maintaining the values of delayed reinforcers. Objective This study aims to examine the effect of AcbC lesions on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes (Killeen 1994 Mathematical principles of reinforcement. Behav Brain Sci 17:105–172). Materials and methods Rats with bilateral quinolinic acid-induced lesions of the AcbC (n = 15) or sham lesions (n = 14) were trained to lever-press for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions), it was two pellets; in Phase 3, (30 sessions) it was one pellet. Results The performance of both groups conformed to the model of progressive-ratio performance (group mean data: r ²  > 0.92). The motor parameter, δ, was significantly higher in the AcbC-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was sensitive to changes in reinforcer size, but did not differ significantly between the two groups. The AcbC-lesioned group showed longer post-reinforcement pauses and lower running response rates than the sham-lesioned group. Conclusions The results suggest that destruction of the AcbC impairs response capacity but does not alter the efficacy of food reinforcers. The results are consistent with recent findings that AcbC lesions do not alter sensitivity to reinforcer size in inter-temporal choice schedules.     

Clozapine increases breaking points on a progressive-ratio schedule reinforced by intravenous cocaine.

The effect of the atypical neuroleptic clozapine on cocaine self-administration reinforced on a progressive-ratio schedule in rats was examined. The rat's first response on a lever each day produced an IV infusion of cocaine (0.6 mg/injection) after which the requirements of the schedule escalated with each infusion until the frequency of responding on the lever fell below a criterion level. The final ratio completed was defined as the breaking point. Doses of 5 and 20 mg/kg clozapine produced either no effect or a nonspecific disruption in responding. Rats pretreated with 10 mg/kg clozapine responded to significantly higher breaking points, indicating an increased motivation to self-administer cocaine.     

Increased breakpoints on a progressive ratio schedule reinforced by IV cocaine are associated with reduced locomotor activation and reduced dopamine efflux in nucleus accumbens shell in rats

Rationale

It has been hypothesized that sensitization of the neurochemical effects within the mesolimbic dopamine (DA) system might account for specific aspects of the addiction process. We have recently developed a self-administration procedure which produces increases in responding reinforced by cocaine on a progressive ratio (PR) schedule. This may reflect an increased motivation to self-administer cocaine, one hallmark of addiction.

Objectives

The goal of this experiment was to investigate behavioral and neurochemical changes associated with increased cocaine self-administration on a PR schedule.

Materials and methods

Rats self-administered cocaine over 14 days under a PR schedule. Cocaine-stimulated locomotor activity was evaluated before as well as 1 or 14 days after self-administration training. Cocaine-induced DA changes in the core and shell of the nucleus accumbens in the same animals were also examined.

Results

Subjects showed increased responding over time, to about 200% of baseline. Cocaine-induced locomotor activation was decreased at both withdrawal times compared to naïve animals. Microdialysis showed no differences after self-administration in the nucleus accumbens core dopamine response at either time point. There was, however, a significant decrease in the dopamine response to cocaine in the shell of the nucleus accumbens.

Conclusion

The present results demonstrate that a progressive increase in breakpoints on a PR schedule can be established in rats at a time when the ability of cocaine to increase extracellular DA levels and stimulate locomotor activity is reduced. Therefore, sensitization of the mesolimbic DA system does not account for the observed change in drug-taking behavior.

     

Nucleus accumbens dopamine and discriminated approach learning: interactive effects of 6-hydroxydopamine lesions and systemic apomorphine administration

RATIONALE: Drug-paired stimuli elicit drug craving and relapse in addicts and drug-seeking behavior in rats. The functional integrity of the basolateral amygdala (BLA) is necessary for reinstatement of cocaine-seeking behavior elicited by cocaine-conditioned stimuli, but not by cocaine itself. It is unclear, however, whether the BLA plays a similar role in reinstatement of heroin-seeking behavior. OBJECTIVES: To this end, we examined the effects of tetrodotoxin (TTX)-induced inactivation of the BLA on conditioned and heroin-primed reinstatement of extinguished heroin-seeking behavior. METHODS: Rats were trained to press a lever for IV infusions of heroin (maintenance dose of 25 microg/infusion) paired with presentations of a light-tone stimulus complex during daily 3-h sessions. Responding was then allowed to extinguish prior to reinstatement testing. Reinstatement of extinguished heroin-seeking behavior (i.e. lever pressing in the absence of heroin reinforcement) was measured in the presence of response-contingent presentation of the heroin-paired stimulus complex alone and then following TTX (5 ng/0.5 microl per side) or vehicle infused into the BLA. In a separate group of rats, reinstatement was measured after saline injection (SC) and then following heroin priming (0.25 mg/kg, SC) with TTX or vehicle infused into the BLA. RESULTS: Both response contingent presentation of the stimulus complex and heroin priming significantly reinstated extinguished heroin-seeking behavior, and BLA inactivation abolished the ability of the heroin-paired stimuli and of heroin priming to reinstate responding. CONCLUSIONS: These findings suggests that the BLA is a critical component of the neural circuitry that mediates conditioned and heroin-induced reinstatement of heroin-seeking behavior. Furthermore, different neural substrates may mediate drug-primed relapse to cocaine versus heroin-seeking behavior.     

Activation of 5-HT(1B) receptors in the nucleus accumbens reduces self-administration of amphetamine on a progressive ratio schedule

Brain serotonin interacts with dopamine function in a complex fashion. Previous work from our laboratory showed that activation of 5-HT(1B) receptors within the nucleus accumbens attenuates the ability of amphetamine to increase responding for conditioned reinforcement. The primary purpose of these experiments was to determine the impact of 5-HT receptor stimulation, with particular focus on 5-HT(1B) receptors in the nucleus accumbens on the reinforcing effect of amphetamine. To this end several experiments determined the effects of injecting 5-HT, and various 5-HT agonists, into the nucleus accumbens on responding for intravenous infusions of amphetamine (60 microg/kg) delivered according to a progressive ratio schedule of reinforcement. Both 5-HT (2.5, 5 and 10 microg) and the selective 5-HT(1B) receptor agonist CP93,129 (0.625, 1.25 and 2.5 microg) dose-dependently reduced responding for amphetamine. Injections of 5-HT but not CP93,129 also reduced responding for food under a similar PR schedule. The 5-HT(1A) agonist 8-OH-DPAT (5 microg) and the nonselective 5-HT(2) agonist DOI (10 microg) failed to alter amphetamine self-administration. Pretreatment with the selective 5-HT(1B/1D) receptor antagonist GR127935 (3 mg/kg) attenuated the ability of 5-HT and CP93,129 to reduce amphetamine self-administration following their injection into the nucleus accumbens. These results extend our previous findings that increasing 5-HT activity in the nucleus accumbens inhibits dopamine-dependent behaviour, and further indicate that activation of 5-HT(1B) receptors is particularly important in this regard.     

Effects of 6-OHDA lesions of the central medial nucleus accumbens on rat intravenous morphine self-administration

The function of dopaminergic innervations of the central medial nucleus accumbens in the processes maintaining intravenous morphine self-administration was assessed by lesioning with 6-OHDA and comparing drug intake with sham-vehicle treated littermates. Localized bilateral lesions of this structure resulted in significant increases in morphine intake shifting the dose-effect relationship to the right with twice the dose necessary to maintain prelesion rates of self-administration. Content of dopamine and dihydroxyphenylacetic acid was decreased in the nucleus accumbens after the lesion, but unchanged in the adjacent pyriform cortex and anterior caudate nucleus-putamen, while serotonin was significantly decreased in the pyriform cortex. High affinity uptake measurements also suggested nucleus accumbens dopaminergic and pyriform cortex serotonergic innervations to be affected by the lesion. The shift to the right in the dose effect relationship after the lesion suggests these neuronal systems to be excitatory to the processes mediating self-administration.     

Compensatory increase in extracellular dopamine in the nucleus accumbens of adult rats with neonatal 6-hydroxydopamine treatment.

To characterize a compensatory function of the dopaminergic system of residual dopamine (DA) neurons in the mesolimbic pathway with DA-depleting lesions, we compared tissue and extracellular concentrations of DA and its metabolites in the nucleus accumbens (NACC) of adult rats with neonatal 6-hydroxydopamine (6-OHDA) treatment with those of control rats with neonatal vehicle treatment using high-performance liquid chromatography. The tissue concentration of DA for 6-OHDA-treated rats was 26.9% of that for the control rats, whereas the extracellular DA was not significantly different from the controls. Furthermore, the extracellular DA concentration in the NACC of 6-OHDA-treated rats was significantly increased compared to the controls following neurotensin (NT) microinjection into the ventral tegmental area (VTA). These results suggest that the extracellular DA of the adult rat brain following neonatal 6-OHDA treatment was compensated for by increasing the release of DA from terminals in the NACC of remaining DA neurons through increased mesolimbic pathway afferents (increased demand), as well as by decreasing the synaptic DA reuptake sites and/or D4 receptors. This study supports our hypothesis that the compensatory mechanism(s) of remaining DA neurons in the mesolimbic system are underlying in behavioral characteristics of adult rats with neonatal depletion of brain DA.     

Effect of orexin-B-saporin-induced lesions of the lateral hypothalamus on performance on a progressive ratio schedule

It has been suggested that a sub-population of orexinergic neurones whose somata lie in the lateral hypothalamic area (LHA) play an important role in regulating the reinforcing value of both food and drugs. This experiment examined the effect of disruption of orexinergic mechanisms in the LHA on performance on the progressive ratio schedule of reinforcement, in which the response requirement increases progressively for successive reinforcers. The data were analysed using a mathematical model which yields a quantitative index of reinforcer value and dissociates effects of interventions on motor and motivational processes. Rats were trained under a progressive ratio schedule using food-pellet reinforcement. They received bilateral injections of conjugated orexin-B-saporin (OxSap) into the LHA or sham lesions. Training continued for a further 40 sessions after surgery. Equations were fitted to the response rate data from each rat, and the parameters of the model were derived for successive blocks of 10 sessions. The OxSap lesion reduced the number of orexin-containing neurones in the LHA by approximately 50% compared with the sham-lesioned group. The parameter expressing the incentive value of the reinforcer was not significantly altered by the lesion. However, the parameter related to the maximum response rate was significantly affected, suggesting that motor capacity was diminished in the OxSap-lesioned group. The results indicate that OxSap lesions of the LHA disrupted food-reinforced responding on the progressive ratio schedule. It is suggested that this disruption was brought about by a change in non-motivational (motor) processes.     

Behavioral activity of some novel aporphines in rats with 6-hydroxydopamine lesions of caudate or nucleus accumbens

The behavioral actions of some novel aporphines have been examined in rats with selective unilateral 6-hydroxydopamine (6OHDA)-induced destruction of nigrostriatal dopaminergic neurons, and in rats with bilateral 6OHDA-induced destruction of mesolimbic dopaminergic neurons. Dopaminomimetics such as apomorphine (APO) in these animal models elicit circling behavior and locomotor activity respectively. In animals with unilateral nigrostriatal lesions (-)-2,10,11-trihydroxy-N-n-propylnoraporphine (TNPA) and (-)-10,11-methylenedioxy-N-n-propylnoraporphine (MDO-NPA) elicited weak, but prolonged, contraversive circling, whereas (-)-2,10,11-trihydroxyaporphine (2-OH.APO) was inactive. In animals with bilateral destruction of mesolimbic dopaminergic neurons TNPA and MDO-NPA elicited a strong stimulation of locomotor activity, while 2-OH.APO was inactive. The results suggest that TNPA and MDO-NPA, but not 2-OH.APO, exert central dopaminomimetic effects in vivo. The results are also consistent with previous data indicating that N-propyl substitution of aporphines causes a relative enhancement of activity in animal models which emphasise effects at mesolimbic rather than striatal dopaminergic receptors.     

Effects of 6-OHDA lesions in the nucleus accumbens on the acquisition of self injection of heroin under schedule and non schedule conditions in rats

Acquisition of heroin self injection is enhanced in bodyweight reduced rats if a non contingent food delivery schedule is operating (schedule-induced self injection). Dopamine depletion of the nucleus accumbens septum (NAS) reduces nicotine self injection and a number of other schedule-induced behaviours. In the present experiment 6-OHDA lesions in the NAS significantly reduced the levels of heroin self injection in 7 rats on a food delivery schedule compared with sham lesioned controls. The reduced heroin intake did not differ from that of lesioned or sham lesioned rats with no schedule present. The results confirm previous reports that intact dopaminergic neurones in the NAS are necessary for schedule-induced behaviours to occur, and demonstrate that components of the same behaviour which are not schedule-induced can continue without disruption in the presence of the lesions.     

Cocaine self-administration reinforced on a progressive ratio schedule decreases with continuous d-amphetamine treatment in rats

Rationale

To date, there is no medication specifically approved for cocaine addiction. Agonist medications are used clinically in the treatment of other addictions, which suggests that this method of drug therapy could potentially be successful in treating cocaine addiction as well.

Objective

The objective of this study was to determine the effect of extended d-amphetamine treatment on responding on a progressive ratio (PR) schedule reinforced by cocaine.

Materials and methods

Rats were trained to self-administer cocaine (0.19, 0.38, 0.75, or 1.5 mg/kg/injection) or food on a PR schedule. After stable baseline breakpoints (the number of reinforcers earned in one session) were established over 3 days, animals were implanted with osmotic mini-pumps that continuously delivered d-amphetamine (5 mg/kg/day) for a duration of either 7 or 14 days. Breakpoints were then determined during and/or after this treatment period.

Results

Rats demonstrated dose-dependent decreases in cocaine-reinforced responding over the d-amphetamine treatment period. Breakpoints for doses of 0.75 mg/kg/injection and below decreased significantly when compared to baseline and remained decreased for up to 14 days after mini-pump removal, whereas those for the highest dose of cocaine remained unchanged. Additionally, d-amphetamine treatment during a 14-day abstinence period from cocaine self-administration had no effect on breakpoints when tested the day after mini-pump removal.

Conclusions

These data suggest that the reduction in cocaine-reinforced responding after continuous d-amphetamine treatment cannot be accounted for by tolerance alone. Instead, the roles of learning and the interaction between cocaine and d-amphetamine must be considered and examined in future studies.     

Toluene-induced locomotor activity is blocked by 6-hydroxydopamine lesions of the nucleus accumbens and the mGluR2/3 agonist LY379268.

The abuse of volatile inhalants remains a prominent, yet poorly understood, form of substance abuse among youth. Nevertheless, the identification of a mechanism underlying the reinforcing properties of inhalants has been hampered by the lack of a clearly identifiable neural substrate upon which these chemicals act. One ingredient that is common to many abused inhalants is toluene, an organic solvent that is self-administered by nonhuman primates and rodents. Most drugs of abuse have been found to elicit forward locomotion in rats, an effect owing to the activation of mesoaccumbal dopamine (DA) pathways. Thus, the present study was undertaken using two different approaches to determine whether toluene-induced locomotor hyperactivity is also ultimately dependent upon DA neurotransmission in the mesolimbic nucleus accumbens (NAC). Here we report on the effects of 6-hydroxydopamine (6-OHDA) lesions of the NAC or pretreatment with the metabotropic mGlu2/3 receptor agonist LY379268 on toluene-induced locomotor activity. Both procedures, which are known to alter neurotransmission within the NAC, significantly attenuated toluene's locomotor stimulatory effects. These results provide strong support for a central mechanism of action of inhalants, which in the past has been more typically attributed to general nonspecific mechanisms throughout the brain. Moreover, as with other drugs of abuse, the NAC may be the final common pathway subserving toluene's abuse liability.     

Effects of 5,7-dihydroxytryptamine lesions of the nucleus accumbens on rat intravenous morphine self-administration

The role of serotonergic innervations of the nucleus accumbens in the processes maintaining intravenous morphine self-administration were assessed. Pairs of male rat littermates were implanted with intravenous jugular catheters and bilateral injection guide cannulae into the central medial nucleus accumbens, made physically dependent on morphine and then allowed to intravenously self-administer with continuous access. When stable baselines of drug intake were obtained (2-3 weeks), one of each pair received bilateral microinjections of vehicle and the other 5,7-dihydroxytryptamine (5,7-DHT) into the nucleus accumbens. Response independent infusions of morphine were delivered for 24 hours at the previous rate of self-injection and the animals were again allowed to self-administer while drug intake was monitored for thirteen days. The littermate pairs were then sacrificed by immersion in liquid nitrogen, the brains removed at -20 degrees C and frozen sections of the cannulae tract taken for histological assessment. The nucleus accumbens, anterior caudate nucleus and pyriform cortex were removed at -20 degrees C and biogenic monoamine content determined. The 5,7-DHT lesions resulted in a significant increase in drug intake and significantly decreased the content of serotonin (5-HT) and 5-hydroxyindoleacetic acid in the nucleus accumbens (-49% and -30%, respectively) and 5-HT in the anterior caudate nucleus (-14%) and pyriform cortex (-17%). Dose-effect relationships were assessed in four additional animals before and after similar bilateral 5,7-DHT lesions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aporphines. 16. Action of aporphine alkaloids on locomotor activity in rats with 6-hydroxydopamine lesions of the nucleus accumbens.

(-)-Apomorphine and (+/-)-N-n-propylnorapomorphine (+/-)-NPA) produce stereotypy but not locomotor activity in normal rats. In rats with selective bilateral lesions of dopamine terminals in the nucleus accumbens induced by microinjection of 6-hydroxydopamine both compounds produced a marked stimulation of locomotor activity. (+/-)-NPA was considerably more potent than (-) -apomorphine. The maximal intensity of stimulation produced by the two drugs was, however, similar. The locomotor stimulant effects of (-)-apomorphine were inhibited by (+)-bulbocapnine (20 mg/kg) or pimozide (0.5 mg/kg). (+/-)-N-n-Propylnorapocodeine also produced a long-lasting stimulation of locomotor activity. (+/-)-Aporphine, (+/-)-isopomorphine, (-)-1,2-dihydroxyaporphine, and (-)-nuciferine were all inactive in stimulating locomotor activity.     

Behavioural effects of electrolytic and 6-hydroxydopamine lesions of the accumbens and caudate-putamen nucleic

Selective bilateral destruction of dopaminergic neuronal terminals in the accumbens nuclei with 6-hydroxydopamine reduced spontaneous and amphetamine-induced locomotor and exploratory behaviour and sniffing activity; amphetamine-induced stereotyped behaviour appeared to be mildly potentiated. Similarly induced bilateral destruction of dopaminergic nerve endings in the caudateputamen reduced spontaneous activity; amphetamine-induced stereotyped behaviour was abolished. Some animals with severe degrees of neostriatal dopamine depletion were completely unresponsive to amphetamine, apart from intense sniffing activity. Bilateral electrolytic lesions of the accumbens nuclei did not alter spontaneous or amphetamine-induced activity.     

The effects of nucleus accumbens core and shell lesions on intravenous heroin self-administration and the acquisition of drug-seeking behaviour under a second-order schedule of heroin reinforcement

RATIONALE: Evidence has implicated the nucleus accumbens (NAcc) in drug-seeking and -taking behaviour. However, the importance of the "core" and "shell" subdivisions of the NAcc in heroin-seeking and -taking behaviour remains unclear. OBJECTIVES: To investigate the function of the NAcc core and shell in heroin self-administration and heroin-seeking behaviour. METHODS: Male rats were trained to self-administer heroin (0.12 mg/kg per infusion) under a continuous reinforcement (CRF) schedule. After responding stabilised, rats were given excitotoxic (or sham) lesions of either the NAcc core or shell and after recovery were assessed for their retention of heroin self-administration under CRF. At this point a second-order schedule of reinforcement was introduced, commencing at FR10 (FR1:S) and terminating at FR10 (FR10:S), in which ten lever presses resulted in presentation of the heroin-associated CS+, and completion of ten such units resulted in drug infusion. RESULTS: Within 7 days, all groups re-acquired responding for heroin under CRF at rates similar to their pre-lesion performance. However, rats with lesions of the NAcc core, but not shell, were severely impaired in the acquisition of heroin-seeking behaviour. CONCLUSIONS: These results indicate an important role for the core of the NAcc in the acquisition of heroin-seeking behaviour under the control of drug-associated stimuli.