The behavioral effects of habituation and challenge with apomorphine after 6-OHDA lesioning of the nucleus accumbens in rats

In rats the function of the dopamine system in the nucleus accumbens was tested after 6-OHDA lesioning of this brain area and after ORG 2766 induced facilitation of recovery in 6-OHDA lesioned animals. A low dose of systematically administered apomorphine (50 μg/kg) decreased motility when sham operated rats were placed in a novel environment. A similar decrease was found in saline treated rats tested for the second time 1 day later. In thus habituated animals, the low dose of apomorphine did not induce hypomotility. Thus habituation and hypomotility after a low dose of apomorphine may be due to a similar mechanism, viz. diminished dopamine release. A higher dose of apomorphine (125 μg/kg) increased motility, but only when the rats were habituated to the test environment. Animals with a bilateral 6-OHDA lesion of the nucleus accumbens showed hypomotility when tested for the first time 1 week after the lesion. The low and the higher dose of apomorphine elicited hypermotility in both nonhabituated and habituated lesioned rats. Their activity was higher than in sham operated animals, suggesting supersensitivity of postsynaptically located dopamine receptor systems in lesioned rats. Treatment with the ACTH(4–9) analog ORG 2766 during the first week after induction of the lesion counteracted the hypomotility of the lesioned rats. Furthermore ORG 2766 enhanced the supersensitivity as revealed by challenge with the low dose of apomorphine.     

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.     

药物干预对6-羟基多巴胺处理大鼠的纹状体细胞外液多巴胺的影响

目的 研究古拉定、川芎嗪、丹参对6—羟基多巴胺(6—OHDA)处理后大鼠的纹状体细胞外液多巴胺(DA)及其代谢产物的影响。方法 运用6—OHDA损毁大鼠黑质，设立正常对照组、6—OHDA损毁组、损毁后古拉定治疗组、川芎嗪治疗组和丹参治疗组。损毁后8周用微透析法采集各组大鼠纹状体细胞外液，用高效液相色谱-电化学法(HPLC—ECD)检测DA、DOPAC、HVA。结果 发现四组损伤组的DA及其代谢产物含量明显低于正常对照组(P＜0．001)，而三组治疗组与非治疗组组间比较无统计学差异(P＞0．05)。结论三种药物不能改变6—OHDA处理后大鼠纹状体细胞外液DA的含量。     

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.     

Abnormal pattern of amphetamine locomotion after 6-OHDA lesion of anteromedial caudate.

6-Hydroxydopamine (6-OHDA) injections into the anteromedial caudate nucleus (AMCN) produced severe loss of dopamine (DA) fibers in this region of the caudate. After a low dose of d'amphetamine (1.5 mg/kg), AMCN 6-OHDA rats made fewer traverses of the length of the activity cage than control rats. In contrast, AMCN 6-OHDA rats interrupted a photocell bema that passed across the middle of the long axis of the activity cage as often as control rats. 6-OHDA injections into the nucleus accumbens (NAc) produced severe loss of DA fibers in NAc without significantly damaging the adjacent anteromedial caudate or olfactory tubercle. After d-amphetamine (1.5 mg/kg), NAc 6-OHDA rats interrupted the photocell beam and traversed the length of the activity cage as frequently as control rats. We conclude that the DA innervation to the anteromedial caudate, but not to the nucleus accumbens, is necessary for that part of the normal locomotor response to a low dose of d'amphetamine that is required for the performance of long traverses of an activity cage.     

The effect of 6-OHDA lesions of the nucleus accumbens septum on schedule-induced drinking,wheelrunning and corticosterone levels in the rat

In a series of four experiments the relationship between 6-OHDA lesions of the nucleus accumbens septum (NAS), schedule-induced behaviors and plasma corticosterone levels was explored. Data from the first experiment show a significant decrease in water intake during a scheduled food delivery test hour for 6-OHDA lesioned groups of rats compared with sham or non-lesioned groups of rats, while during the remaining 23 hours of the day water intake was the same for 6-OHDA lesioned and sham lesioned groups. In a second experiment similar decreases in schedule-induced wheelrunning were observed for 6-OHDA lesioned rats when compared with sham lesioned rats. Data from a third experiment showed significant increases in plasma corticosterone levels of rats in the presence of a scheduled food delivery compared with rats given non-scheduled food. In a fourth experiment it was shown that 6-OHDA lesions of the NAS abolish this increase of corticosterone levels in rats on a food delivery schedule. These data extend the findings of Robbins and Koob [19] and show a more general involvement of the dopaminergic pathways of the NAS in schedule-induced behaviors and in concomitant plasma corticosterone changes.     

Effects of dopaminergic nucleus accumbens lesions on the acquisition of schedule induced self injection of nicotine in the rat

Data from recent experiments show that dopaminergic depletion of the nucleus accumbens septum (NAS) decreases the frequency of schedule induced drinking and wheel running. In the present experiment a group of 8 rats with 6-OHDA lesions in the NAS showed a significantly lower rate of schedule induced nicotine self injection than sham operated controls. These findings extend the number of schedule induced behaviors which appear to depend for their occurrence on an intact dopamine system in the NAS.     

CCK-8 injected into the nucleus accumbens attenuates the supersensitive locomotor response to apomorphine in 6-OHDA and chronic-neuroleptic treated rats

Postsynaptic dopamine-cholecystokinin (CCK) interactions in the nucleus accumbens were studied in two behavioral preparations of DA receptor supersensitivity: chronic-neuroleptic treated and 6-hydroxydopamine (6-OHDA) denervated rats. Subcutaneous (SC) injections of apomorphine (APO; 0.15 mg/kg) in experiment 1 produced marked hyperlocomotion in rats following 12 days of pretreatment with cis-[Z]-flupenthixol (2 mg/kg; twice per day). Bilateral intra-accumbens (N.Acc.) microinjections of CCK-8 (2 ng and 2 g) reliably reduced APO-stimulated hyperlocomotion. An intermediate CCK dose (20 ng) was without effect. No change in APO responsivity following chronic vehicle treatment was observed and the baseline APO response was not altered by CCK at any dose. Denervation of mesolimbic dopamine (DA) terminals by intra-N.Acc. injections of 6-hydroxydopamine (6-OHDA; 8 g/side) in experiment 2 similarly resulted in intense locomotor hyperactivity after APO stimulation (0.1 mg/kg; SC). Bilateral intra-N.Acc. injections of CCK-8 (1, 10, 100 ng, and 1 g) significantly attenuated the supersensitive locomotor response to APO. As in experiment 1, CCK produced biphasic dose-response effects with strong attenuation that persisted throughout the entire 60-min test at both high (1 g) and low (1 ng) doses. Intermediate CCK doses (10 and 100 ng) produced only shortterm reductions in activity. Hypomotility induced by APO in SHAM-lesioned rats was not effectively reversed by CCK treatments. CCK had no effect on unstimulated baseline locomotor activity in either 6-OHDA or SHAM-lesioned rats. These results provide further evidence that CCK-8 modulates mesolimbic DA activity by functionally opposing the postsynaptic effects of DA in the region of the nucleus accumbens.     

Alcohol drinking attenuated by sertraline in rats with 6-OHDA or 5,7-DHT lesions of N. accumbens: A caloric response?

The purpose of this study was to elucidate further the role of serotonin (5-HT) in the preference for ethyl alcohol induced in the Sprague-Dawley rat by lesions of the N. accumbens. Following a standard preference test for 3–30% alcohol, dopaminergic or serotonergic neurons in the N. accumbens of the rat were lesioned bilaterally by 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT), respectively. After recovery postoperatively, each rat was offered water and its maximally preferred concentration of alcohol, which ranged from 7% to 11%. Following a 4-day pretest, either the saline control vehicle or the 5-HT reuptake inhibitor, sertraline, was injected subcutaneously in a dose of either 3.0 or 10 mg/kg b.i.d. at 0800 and 2000 h over the next 3 days. Alcohol preference during the injection sequence and for 4 days thereafter was significantly reduced by sertraline in terms of both absolute g/kg and proportion of alcohol to water intakes. Saline was without effect on alcohol drinking. Comparisons of the drinking profiles of serotonergic versus dopaminergic lesioned rats revealed a dose dependent response to sertraline only in the 5,7-DHT lesioned animals. Although sertraline did not alter water drinking, the consumption of food declined significantly during and after its administration with a decline in body weight also observed at the higher dose. These results suggest that in addition to dopaminergic neurons in the N. accumbens, the synaptic activity of 5-HT in this structure contributes to the aberrant drinking of alcohol. However, this interpretation is tempered by the fact that caloric intake was suppressed concomitantly by the drug. Thus the presumed central action of sertraline may not be functionally specific to the reinforcing or other behavioral properties of alcohol.     

Effects of dopamine receptor stimulants on locomotor activity of rats with electrolytic or 6-hydroxydopamine-induced lesions of the nucleus accumbens

Ergometrine (8 mg/kg) injected intraperitoneally into normal rats had little effect on locomotor activity. In contrast, rats with selective 6-hydroxydopamine-induced lesions of dopamine terminals in the nucleus accumbens showed a strong stimulation of locomotor activity following injection of this dose of ergometrine.The dopamine analogue 2-amino-6-7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) (150 g), caused strong and long lasting stimulation of locomotor activity when injected intracerebroventricularly into rats. The ADTN response was markedly reduced in rats with bilateral electrolytic lesions of the nucleus accumbens, but unchanged in rats with bilateral electrolytic lesions of the caudate nucleus. At a lower dose level (50 g) ADTN, injected intracerebroventricularly, had little effect on the locomotor activity of normal or sham-operated rats. This dose of ADTN was, however, effective in causing locomotor stimulation of rats with bilateral 6-hydroxydopamine-induced lesions of the nucleus accumbens.These results support the view that the dopamine receptors in the nucleus accumbens are involved in the actions of locomotor stimulant drugs.     

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.     

Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward

 Microinjections of phencyclidine (PCP) into the ventro-medial portion of nucleus accumbens in rats potentiated the rewarding impact of lateral hypothalamic brain stimulation. Similar effects were found with nomifensine, which shares with PCP the ability to block dopamine uptake and thus elevate synaptic dopamine levels but does not share with PCP the ability to block NMDA receptors. Similar effects were also seen with dizocilpine (MK-801) and [3-((±)2-carboxypiperazin-4-yl)propyl-1-phosphonate] (CPP), which share with PCP the ability to block NMDA receptors but not to block dopamine uptake. Thus PCP’s properties as a dopamine uptake inhibitor and as an NMDA receptor antagonist each appear capable of producing reward-related actions in this brain region. The common denominator of these two PCP actions is decreased output of medium spiny neurons; these neurons are tonically activated by a glutamate projection from prefrontal cortex (PCP blocks this source of activation) and are tonically inhibited by a dopaminergic projection from the ventral tegmental area (PCP augments this inhibition). Received: 10 April 1996 / Final version: 5 August 1996     

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 chronic buprenorphine treatment on levels of nucleus accumbens glutamate and on the expression of cocaine-induced behavioral sensitization in rats

Rationale

Chronic treatment with the mu-opioid receptor agonist, buprenorphine, reduces cocaine-induced behaviors in rats with a history of cocaine self-administration. The mechanisms underlying these actions of buprenorphine remain unclear.

Objectives

The objective of this study is to investigate the effects of chronic buprenorphine treatment on cocaine-induced activity and levels of glutamate and dopamine (DA) in the nucleus accumbens (NAc) in rats that were preexposed to cocaine or drug-naïve.

Materials and methods

In experiment 1, basal levels of NAc glutamate were assessed using in vivo microdialysis in cocaine-naïve rats that were treated chronically with buprenorphine (3.0 mg/kg per day) via osmotic minipumps or that underwent sham surgery. In experiment 2, rats were preexposed to seven daily injections of cocaine or saline. After a 12–16-day drug-free period, extracellular levels of NAc glutamate and DA and locomotor activity were assessed simultaneously, before and after an acute injection of cocaine (15 mg/kg, intraperitoneal), in rats under sham and chronic buprenorphine (3.0 mg/kg per day) treatment.

Results

Chronic buprenorphine treatment increased basal levels of glutamate in drug-naïve and cocaine-preexposed rats, blocked the expression of locomotor sensitization to cocaine, and potentiated the NAc DA response to acute cocaine in cocaine-preexposed rats.

Conclusions

These findings suggest that buprenorphine may block the expression of cocaine sensitization and other cocaine-related behaviors by increasing basal levels of glutamate in the NAc, which would serve to decrease the effectiveness of cocaine or cocaine-associated cues.     

Activation of 5-HT1B receptors in the nucleus accumbens reduces amphetamine-induced enhancement of responding for conditioned reward

Previously, we have demonstrated that 5-hydroxytryptamine (5-HT) injected into the nucleus accumbens attenuates the potentiating effects of d-amphetamine on responding for conditioned reward (CR). The present studies examined the 5-HT receptor involved in this effect by investigating the effects of 5-HT agonists with differing affinities for 5-HT₁ and 5-HT₂ receptors on d-amphetamine-induced potentiation of responding for CR. Rats were trained to associate a light/tone stimulus (subsequently the CR) with water delivery. In a test phase, they were allowed access to a lever delivering the CR, and an inactive (NCR) lever. Responding on the CR lever was greater than responding on the NCR lever, indicating that the light/tone stimulus functioned as a CR. Responding for the CR was selectively potentiated by injections of d-amphetamine (10 μg) into the nucleus accumbens. This effect was reduced by injections into the nucleus accumbens of 5-CT (0.5 and 1 μg), RU24969 (10 μg), CP93,129 (1.25 and 2.5 μg) but not by DOI (10 μg) or 8-OH-DPAT (5 μg). The lower doses of 5-CT and CP93,129 did not reduce baseline responding for CR, or responding for water in a separate group of animals, indicating that the effects of these drugs were behaviourally selective. The higher doses abolished the CR effect, and in the case of 5-CT and RU24969 also reduced responding for water. All of the effective drugs share in common the ability to stimulate 5-HT_1B receptors, albeit with differing selectivities. The effect of CP93,129, the most selective of the 5-HT_1B agonists, to inhibit the response-potentiating effect of d-amphetamine was reversed by the5-HT_1B/1D antagonist GR127935 (3 mg/kg). The results indicate that activation of 5-HT_1B receptors within the nucleus accumbens attenuates the effects of a dopamine-dependent behaviour, and that activation of these receptors can oppose the behavioural effects of elevated mesolimbic dopamine transmission. Received: 22 April 1998/Final version: 28 July 1998     

Time-dependent recovery from the effects of 6-hydroxydopamine lesions of the rat nucleus accumbens on cocaine self-administration and the levels of dopamine in microdialysates

Rationale Neurotoxin induced lesions of dopamine-releasing neurons that innervate the nucleus accumbens (NAcc) alter cocaine self-administration. In addition, elevated extracellular levels of NAcc dopamine (DA) are thought to be central to the biological mechanisms that underlie this behavior.Objectives This study assessed the long-term effects of 6-hydroxydopamine (6-OHDA) induced lesions of the NAcc on cocaine self-administration and the dialysate levels of dopamine ([DA]_d) in this structure to determine if recovery of drug intake was correlated with the DA response.Methods Rats implanted with jugular catheters and bilateral cannulas were trained to self-administer cocaine and subsequently received bilateral intracranial micro-injections of 6-OHDA or vehicle into the NAcc. The levels of DA and cocaine were determined in microdialysates of the NAcc collected during experimental sessions 6–7, 14–16, 29–30, and 44–46 days post-treatment.Results The 6-OHDA induced lesions significantly reduced cocaine self-administration for 3 weeks while vehicle treatment had a moderate effect for the first several days. Cocaine-induced increases in NAcc [DA]_d did not return to sham/vehicle treated control levels for 6 weeks in the lesioned group and DA content in the NAcc was 46% of control at 44 days post-lesion.Conclusions Although dopaminergic lesions of the NAcc produced profound effects on cocaine self-administration, responding recovered to control levels before cocaine-induced increases in NAcc [DA]_d while content of DA in the NAcc did not recover. These data suggest that the plasticity of neuronal systems in the NAcc related to cocaine self-administration and their response following 6-OHDA lesions is more complex than restoration of DAergic tone.     

Injection of 5-HT into the nucleus accumbens reduces the effects ofd-amphetamine on responding for conditioned reward

Injection ofd-amphetamine into the nucleus accumbens potentiates responding for stimuli paired with a primary reward. A previous study showed that this potentiating effect ofd-amphetamine on responding for conditioned reward (CR) was attenuated by peripherally injectedd-fenfluramine, a 5-hydroxytryptamine (5-HT) releaser and re-uptake inhibitor. The present experiments further examined the effects of manipulating 5-HT function within the nucleus accumbens on responding for CR, and on the potentiation of CR responding following intra-accumbens injection ofd-amphetamine. Water deprived rats were trained to associate a compound stimulus with water delivery during a conditioning phase. During a test phase water was not delivered, but the compound stimulus was delivered according to a random ratio 2 schedule following a response on one of two levers. Rats responded at a higher rate on the lever delivering this CR.d-Amphetamine (10 g) injected into the nucleus accumbens enhanced responding on the CR lever. Co-injections of 5-HT (5 and 10 g) into the nucleus accumbens abolished the response-potentiating effect ofd-amphetamine but were without effect on the base-line level of responding for CR. This reduction by 5-HT of the response potentiating effect ofd-amphetamine was prevented by prior treatment with the 5-HT receptor antagonist metergoline (1 mg/kg). Responding for water was not altered by 5-HT and so the effects of 5-HT on responding for CR cannot be due to a change in the motivation to seek the primary reward. Thus, elevating 5-HT activity within the nucleus accumbens antagonises the effects ofd-amphetamine on responding for CR within the nucleus accumbens. These results suggest that 5-HT within the nucleus accumbens may play an important role in mediating incentive motivation by modulating dopaminergic neurotransmission.     

The stimulation of cholecystokinin receptors in the rostral nucleus accumbens significantly antagonizes the EEG and behavioural effects induced by phencyclidine in rats

The influence of cholecystokinin (CCK), bilaterally injected into the rostral nucleus accumbens, on the EEG and behavioural effects induced by phencyclidine (PCP) has been studied in rats. CCK (10 ng) significantly inhibited PCP-induced EEG effects (increase of spectral power with respect to pre-drug tracing; increase of relative power distribution in the slowest frequency bands), and behavioural effects (circling and ataxia). The inhibitory effects of CCK were completely antagonized by 1 ng PD 135–158, a selective CCK_B receptor antagonist, but not by lorglumide (1 µg), a selective CCK_A receptor antagonist. Since the effects induced by PCP in rodents have been proposed to be an experimental correlate of the psychotic symptoms it induces in humans, these results indicate that CCK may act as a neuroleptic. They also suggest that CCK_B receptors located in the rostral nucleus accumbens may be involved in the neuroleptic-like activity of CCK.     

Role of nucleus accumbens dopamine D1 and D2 receptors in instrumental and Pavlovian paradigms of conditioned reward

RATIONALE: This study investigated the role of nucleus accumbens dopamine D1 and D2 receptors in two different paradigms of conditioned reward. OBJECTIVE: We addressed the question whether accumbal dopamine is important for the motor or for the motivational components of reward. METHODS: We compared the effects of intra-accumbal infusion of the dopamine D1 receptor antagonist SCH23390 (0.3, 1.0, 3.0 microg) and the D2 receptor antagonist sulpiride (0.3, 1.0, 3.0 microg) on conditioned lever pressing for food, with the effects on the inhibition of the startle response by a conditioned reward signal. RESULTS: Both the D1 and the D2 antagonist dose-dependently attenuated conditioned lever pressing for reward under a fixed-ratio of responding and increased the consumption of freely available lab chow. However, the preference for freely available pellets, and the attenuation of the startle response in the presence of a conditioned stimulus predicting reward were not impaired by blockade of accumbal dopamine receptors. CONCLUSIONS: Our data support the idea that dopamine in the nucleus accumbens is necessary for instrumental response selection in the context of reward rather than for the mere motor performance of behavior or for the evaluation of the hedonic properties of rewarding stimuli.     

Mesolimbic dopamine neurons: Effects of 6-hydroxydopamine-induced destruction and receptor blockade on drug-induced rotation of rats

Bilateral injections of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens greatly reduced the dopamine content of this nucleus and the olfactory tubercle and blocked the ipsilateral rotation induced by amphetamine and methamphetamine in rats with unilateral 6-OHDA lesions of the caudate nucleus. In contrast, apomorphine-induced contralateral rotation was enhanced. Similar results were obtained when the destruction of forebrain noradrenergic neurons, normally produced by the nucleus accumbens 6-OHDA lesion, was prevented by desipramine (DMI) pretreatment. Microinjections of the dopamine receptor antagonist haloperidol into the nucleus accumbens did not spread to the olfactory tubercle, as assessed by the distribution of ³H-haloperidol, and blocked circling induced by amphetamine and apomorphine. Amphetamine-induced circling was less effectively blocked by haloperidol injected into the olfactory tubercle. These results suggest that activity at nucleus accumbens dopamine receptors can greatly affect circling behavior, perhaps by amplifying asymmetries of nigrostriatal activity.