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Rationale: Despite the critical role attributed to phosphorylated extracellular signal regulated kinase (pERK1/2) in the nucleus accumbens (Acb) in the actions of addictive drugs, the effects of morphine on ERK1/2 phosphorylation in this area are still controversial., Objectives: In order to investigate further this issue, we studied (1) the ability of morphine to affect ERK1/2 phosphorylation in the shell (AcbSh) and core (AcbC) of Sprague-Dawley and Wistar rats and of CD-1 and C57BL/6J mice and (2) the role of dopamine D1 and μ-opioid receptors in Sprague-Dawley rats and CD-1 mice., Methods: The pERK1/2 expression was assessed by immunohistochemistry., Results: In rats, morphine decreased AcbSh and AcbC pERK1/2 expression, whereas in mice, increased it preferentially in the AcbSh compared with the AcbC. Systemic SCH 39166 decreased pERK1/2 expression on its own in the AcbSh and AcbC of Sprague-Dawley rats and CD-1 mice; furthermore, in rats, SCH 39166 disclosed the ability of morphine to stimulate pERK1/2 expression. Systemic (rats and mice) and intra-Acb (rats) naltrexone prevented both decreases, in rats, and increases, in mice., Conclusions: These findings confirm the differential effects of morphine in rats and mice Acb and that D1 receptors exert a facilitatory role on ERK1/2 phosphorylation; furthermore, they indicate that, in rats, removal of the D1-dependent pERK1/2 expression discloses the stimulatory influence of morphine on ERK1/2 phosphorylation and that the morphine's ability to decrease pERK1/2 expression is mediated by Acb μ-opioid receptors. Future experiments may disentangle the psychopharmacological significance of the effects of morphine on pERK1/2 in the Acb.

Rationale: The only systematic in vivo studies comparing antipsychotic (AP) effects on nucleus accumbens (NAc) shell and core dopamine (DA) transmission are voltammetric studies performed in pargyline-pretreated, halothane-anaesthetized rats. Studies in freely moving rats not pretreated with pargyline are not available. This study was intended to fill this gap by the use of in vivo microdialysis in freely moving rats., Methods: Male Sprague-Dawley rats were implanted with microdialysis probes in the NAc shell and core and medial prefrontal cortex (PFCX). The next day, rats were administered intravenously with two or three doses of APs, and dialysate DA was monitored in 10-min samples. Some rats were pretreated with pargyline (75 mg/kg i.p.) and after 1 h were given clozapine or risperidone., Results: Clozapine, risperidone, quetiapine, raclopride, sulpiride and amisulpride increased DA preferentially in the NAc shell. Such preferential effect on shell DA was not observed after haloperidol, chlorpromazine and olanzapine. In contrast to voltammetric studies, a preferential effect on NAc core DA was not observed after any dose of AP. Pargyline pretreatment did not reduce but actually amplified the preferential effect of clozapine and risperidone on NAc shell DA., Conclusions: Apart from raclopride and olanzapine, the APs with lower extrapyramidal effects could be distinguished from typical APs on the basis of their ability to preferentially stimulate DA transmission in the NAc shell. There was no relationship between stimulation of PFCX DA and atypical APs profile. The differences between this study and voltammetry studies were not attributable to pargyline pretreatment.

Rationale: Sensitization of the incentive and dopamine (DA) stimulant properties of drug-conditioned stimuli (CSs) by repeated exposure to drugs of abuse has been assigned an important role in the genesis of drug addiction., Objective: To test in rats if morphine-induced sensitization potentiates incentive and DA-releasing properties in the nucleus accumbens (NAc) shell and core elicited by presentation of a morphine-conditioned stimulus(CS) and if this property generalizes to a non-drug-(palatable food, Fonzies)-CS., Methods: Controls and rats previously sensitized by morphine were trained via three daily sessions consisting of a 10-min presentation of CS (Fonzies filled box, FB) followed by s.c. saline and morphine (1 mg/kg) or by standard food and Fonzies. Rats were implanted with microdialysis probes and the next-day incentive reactions and NAc shell and core DA were monitored during CS presentation and subsequent morphine (1 mg/kg) administration or Fonzies feeding., Results: Morphine sensitization increased incentive and NAc shell and core DA responses to morphine-CS. Morphine conditioning per se increased incentive reactions and NAc shell but not core DA responses to FB presentation. Morphine sensitization potentiated incentive responses but did not affect NAc shell and core DA responses to Fonzies-CS. Fonzies conditioning increased incentive reactions and NAc core but not shell DA responses to FB presentation., Conclusions: These observations confirm the prediction of the incentive sensitization theory in the case of drug-CS but not of non-drug-CS. NAc DA might be differentially involved in the expression of incentive sensitization of drug- and non-drug-CSs, thus providing a clue for the abnormal incentive properties of drug CSs.

Rationale: Repeated treatment with morphine has been shown to sensitize rats to its stimulant effects on motor activity and mesolimbic dopamine (DA) transmission., Objectives: The aim of this study is to investigate if morphine sensitization is associated to changes in the behavioral reactions to appetitive and aversive taste stimuli and in the response of in vivo DA transmission in the nucleus accumbens (NAc) shell and core and medial prefrontal cortex (PFCX) to the same stimuli., Methods: Rats were administered twice a day for three consecutive days with increasing doses of morphine [10, 20, and 40 mg/kg, subcutaneously (sc)] or with saline. After 15 days of withdrawal, rats were infused intraorally with either an appetitive (sweet chocolate, 1 ml) or an aversive solution (quinine HCl 5 × 10(-4) M, 1 ml). The behavioral taste reactions were recorded during microdialysis of DA in the NAc shell and core and PFCX., Results: Opiate sensitization did not affect behavioral reactions to intraoral chocolate or quinine. In rats naive to the taste stimuli, morphine sensitization was associated to potentiation of stimulatory DA response to appetitive and aversive taste stimuli in the NAc core. Morphine sensitization reciprocally affected habituation of DA responsiveness after one trial exposure to appetitive and aversive taste stimuli (abolition it in the shell, induction in the PFCX). No habituation of DA responsiveness to taste was observed in the NAc core in controls as well as in morphine-sensitized rats., Conclusions: These results suggest that opiate sensitization is associated to differential adaptive changes of the responsiveness of DA transmission to taste stimuli in DA terminal areas.

Rationale: Drugs of abuse and palatable food share the ability to stimulate dopamine (DA) transmission in the nucleus accumbens shell. However, while the stimulation of shell DA by food undergoes habituation, that by drugs of abuse does not., Objective: This study aims to directly compare the changes of extracellular DA, by microdialysis, in shell and core and prefrontal cortex (PFCX) in response to food- and drug-conditioned stimuli (CSs)., Methods: Rats were trace-conditioned by Fonzies box (FB) or vanilla box (VB; CS), followed by food: Fonzies, intraoral chocolate solution (food-unconditioned stimulus (US)) and morphine (1.0 mg/Kg sc; drug US). Control (unconditioned) rats received standard food instead of Fonzies, tap water instead of chocolate, saline instead of morphine., Results: Food-CSs increased core but not shell DA, while drug-CSs did the opposite. Food and drug-CSs both increased PFCX DA. Exposure to food-CSs potentiated core and PFCX DA response to food while shell responsiveness was dependent upon the relative CS and US nature. If the CS was intrinsic to the food US (CS = FB/US = Fonzies) the response of shell DA to the US was abolished. If the CS was extrinsic to the food US (CS = FB/US = chocolate; CS = VB/US = Fonzies), shell DA increased in response to the US. Exposure to the drug-CS potentiated the DA response to the drug-US in the shell and in the PFCX, but not in the core., Conclusion: Drug-CSs differentially activate DA as compared to food-CSs in shell and core and differentially affect DA response to the US in these areas. These differences might be relevant for the role of DA in the mechanism of drug addiction.

Rationale: Although passive administration of heroin to drug-naive rats increases extracellular dopamine (DA) in the nucleus accumbens (NAc), its ability to do so also after active drug exposure (self-administration) is debated., Objectives: This study investigated by repeated microdialysis sampling the inter- and intrasession changes in the responsiveness of the NAc shell and core DA and the behavioral effects of active and passive heroin exposure in the intravenous self-administration/yoked paradigm., Materials and Methods: Rats were implanted with jugular catheters and bilateral intracerebral chronic guide cannulae. Nose poking in the active hole by master rats resulted in heroin administration to the same subjects and to their yoked mates. Concentric microdialysis probes were inserted daily in the guide cannulae, and changes in dialysate DA in response to heroin exposure (0.05 mg/kg) were monitored in the same subject for 90 min for 4 weeks. Behavior associated with heroin exposure, distinguished into nonstereotyped and stereotyped, was also recorded., Results: Dialysate DA increased preferentially in the shell of master rats from the first session (+112%) and throughout the 4 weeks of self-administration (+130-140%). In yoked rats, a preferential but lesser increase in DA in the shell was observed only on the first session (+60%), as the DA response in the NAc core increased progressively (+25-118%), so that within a week, the shell/core ratio was reversed, and this pattern was maintained for the following 2 weeks. Yoked rats showed a progressive and larger increase in stereotyped behaviors than master rats., Conclusions: Chronic heroin self-administration increases extracellular DA preferentially in the NAc shell. Response-noncontingent heroin administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.

Rationale: Conditioned stimuli (CSs) by pavlovian association with reinforcing drugs (US) are thought to play an important role in the acquisition, maintenance and relapse of drug dependence., Objective: The aim of this study was to investigate by microdialysis the impact of pavlovian drug CSs on behaviour and on basal and drug-stimulated dopamine (DA) in three terminal DA areas: nucleus accumbens shell, core and prefrontal cortex (PFCX)., Methods: Conditioned rats were trained once a day for 3 days by presentation of Fonzies filled box (FFB, CS) for 10 min followed by administration of morphine (1 mg/kg), nicotine (0.4 mg/kg) or saline, respectively. Pseudo-conditioned rats were presented with the FFB 10 h after drug or saline administration. Rats were implanted with microdialysis probes in the shell, core and PFCX. The effect of stimuli conditioned with morphine and nicotine on DA and on DA response to drugs was studied., Results: Drug CSs elicited incentive reactions and released DA in the shell and PFCX but not in the core. Pre-exposure to morphine CS potentiated DA release to morphine challenge in the shell but not in the core and PFCX. This effect was related to the challenge dose of morphine and was stimulus-specific since a food CS did not potentiate the shell DA response to morphine. Pre-exposure to nicotine CS potentiated DA release in the shell and PFCX., Conclusion: The results show that drug CSs stimulate DA release in the shell and medial PFCX and specifically potentiate the primary stimulant drug effects on DA transmission.

Rationale: In naive rats, passive administration of drugs of abuse preferentially increases extracellular dopamine (DA) in the nucleus accumbens (NAc) shell as compared to the core. Repeated exposure to the same drugs results in behavioral and biochemical sensitization characterized by stereotyped activity and reduction of the shell/core DA response ratio., Objectives: The aim of this work is to study the neurochemical and behavioral effects of response-contingent vs response-noncontingent drug administration in rats, who were bilaterally implanted with chronic intracerebral guide cannulae and trained to self-administer cocaine by nose poking in daily 1-h sessions for 3 weeks (5 days/week). Nose poking in the active hole by master rats resulted in intravenous injection of cocaine (0.25 mg/kg) in master rats and in rats yoked to them. Dialysate DA was monitored before, during, and for 30 min after cocaine availability on alternate days by inserting the probe into the NAc shell and core. Stereotyped and non-stereotyped behavior was recorded during the sessions., Results: In master rats, dialysate DA increased preferentially in the NAc shell during cocaine self-administration throughout the 3 weeks of cocaine exposure. In yoked rats, DA increased preferentially in the shell but to a lesser extent than in master rats. With continued exposure to cocaine, the shell/core ratio of DA changes decreased progressively and, on the third week, was reversed so that DA increased more in the core than in the shell. Yoked rats showed a progressive and faster increase in stereotyped behaviors than master rats., Conclusions: Response-noncontingent cocaine administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.

Rationale: WIN 55,212-2, a potent cannabinoid receptor 1 agonist, is self-administered by animals to evaluate abuse liability of cannabinoids, but to date no information is yet available about its effects on dopaminergic transmission during active response-contingent administration., Objectives: This study monitored the changes of extracellular dopamine (DA) in the nucleus accumbens (NAc) shell and core during active intravenous WIN 55,212-2 self-administration (SA)., Methods: Rats, implanted with a jugular catheter and bilateral intracerebral chronic cannulae, were trained for 3 weeks to self-administer WIN 55,212-2 (12.5 microg/kg) in single daily 1-h sessions under a fixed ratio 1 (FR 1) schedule, than switched to FR 2 for a further week. During SA sessions, microdialysis assays were performed every 3rd day, and then daily starting from the 13th session. Dialysate DA from the NAc shell and core was monitored before, during, and for 30 min after SA., Results: Dialysate DA increased during WIN 55,212-2 SA starting from the 1st week in the NAc shell and on the 2nd week in the core. The increase of dialysate DA in the NAc shell was larger than that in the core on all weeks. Dialysate DA did not change during extinction sessions in spite of active nose poking., Conclusions: Response-contingent WIN 55,212-2 SA preferentially increases the NAc shell DA output as compared to that of the core independently from the duration of the WIN 55,212-2 exposure. Increase in NAc DA is strictly related to WIN 55,212-2 actions because it is not observed during extinction despite active responding.

Rationale: A large body of evidence indicates an involvement of the mesolimbic dopamine (DA) pathway innervating the ventral striatum in the motivational effects of drug abuse., Objective: The goal of the study is to clarify the role of DA D1 and D2 receptors of the rat nucleus accumbens (NAc) shell and core in the motivational effects of morphine as studied by conditioned place preference (CPP)., Methods: The effect of the intracerebral infusion of DA antagonists specific for DA D1 (SCH 39166) and D2 receptors (L-sulpiride) was studied in a single-trial place conditioning paradigm with fixed assignment of the drug to the unpreferred compartment., Results: Morphine induced significant CPP at all the doses tested (0.5, 1.0, and 2.0 mg/kg, subcutaneously). A dose of 1.0 mg/kg was selected for further studies. Intra-NAc shell infusion of SCH 39166 and L-sulpiride at doses of 25 and 50 ng/1 microl per side impaired the acquisition of CPP by morphine. No effect was observed at 12.5 ng/1 microl per side. Intra-NAc core infusion of SCH 39166 (12.5, 25, and 50 ng/1 microl per side) did not affect the acquisition of morphine-induced CPP, while L-sulpiride (12.5, 25, and 50 ng/1 microl per side) impaired CPP acquisition only at the dose of 50 ng/1 microl per side. No effect on morphine-induced CPP was observed when the DA antagonists were infused into the NAc shell or core 10 min before the test session., Conclusion: These results indicate that DA D1 and D2 receptors in the NAc shell are involved in the acquisition of morphine-induced CPP.

Rationale: Experimental evidence indicates that the mesolimbic dopamine (DA) pathway innervating the ventral striatum is critically involved in the motivational effects of drug abuse. However, the role of DA transmission of the two main subdivisions of the nucleus accumbens (NAc), the shell and the core, in the motivational properties of nicotine is unknown., Objectives: The aim of this study was to investigate the role of DA D1 and D2 receptors of the rat NAc shell and core in the motivational effects of nicotine using a conditioned place preference (CPP) paradigm., Methods: The effect of the intracerebral infusion of DA antagonists specific for DA D1 (SCH 39166) and D2 receptors (L-sulpiride) was studied in a single-trial place-conditioning paradigm with fixed assignment of the drug to the unpreferred compartment., Results: Nicotine induced significant CPP at the dose of 0.4 and 0.6 mg/kg subcutaneously (s.c.). Intra-NAc shell infusion of SCH 39166 (6.25, 12.5, 25 and 50 ng bilaterally, 10 min before nicotine administration), impaired in a dose-dependent manner the acquisition of CPP by nicotine (0.4 mg/kg s.c.). SCH 39166 failed to affect nicotine CPP when infused into the NAc core. L-sulpiride (25 and 50 ng bilaterally) had no effect on acquisition after intra-Nac shell infusion. SCH 39166 and L-sulpiride were ineffective after infusion in the NAc shell and core 10 min before the test session., Conclusions: The results indicate that dopamine D1 but not D2 receptors of the NAc shell are specifically involved in the acquisition of nicotine-induced CPP.

Rationale: It has been reported that passive administration of nicotine increases preferentially extracellular dopamine (DA) release in the shell as compared to that in the core of the nucleus accumbens (NAc). To date, no information is available if this also applies to active, response-contingent nicotine administration., Objective: This study was aimed to monitor the changes of extracellular DA in the NAc shell and core during active intravenous nicotine self-administration (SA)., Methods: Rats were bilaterally implanted with chronic cannulae and were trained to self-administer nicotine (0.03 mg/kg, i.v.) in single daily 1-h session for 6 weeks, with an initial fixed ratio (FR) 1 schedule increased to FR 2. Dialysate DA from the NAc shell and core was monitored before and for 90 min after the start of SA., Results: Significant increases of active nose-pokes over inactive ones were found starting from the 16th SA session. No differences were found in basal extracellular DA in the NAc subdivisions. Data analysis showed (1) significant increases over basal of dialysate DA in the NAc subdivisions during nicotine SA, starting from the first week in the shell and from the second week in the core, (2) preferential increase of extracellular DA during nicotine SA in the shell (24-43%) compared to that in the core (10-23%) and (3) no change in dialysate DA in NAc subdivisions during extinction., Conclusions: Response-contingent nicotine SA preferentially increases the DA output in the NAc shell as compared to that in the core, independently from the duration of the nicotine exposure. Increase in NAc DA is strictly related to nicotine action since is not observed during extinction in spite of active responding.

Rationale: Repeated exposure to several drugs of abuse has been reported to induce behavioural sensitization. So far no evidence has been provided that such a phenomenon also applies to cannabinoids., Objectives: In this study we investigated if repeated exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC) induces behavioural sensitization. In addition we tested the possibility of cross-sensitization between Delta(9)-THC and morphine., Methods: Male Sprague-Dawley rats were administered for 3 days, twice daily, with increasing doses of Delta(9)-tetrahydrocannabinol (2, 4 and 8 mg/kg i.p.) or increasing doses of morphine (10, 20 and 40 mg/kg s.c.) or vehicle. After a washout of 14 days the animals were challenged with Delta(9)-THC (75 and 150 microg/kg i.v.), with a synthetic cannabinoid agonist WIN55212-2 (75 and 150 microg/kg i.v.) or with morphine (0.5 mg/kg i.v.), through a catheter inserted into the left femoral vein 24 h before, and the behaviour recorded., Results: Rats previously administered with Delta(9)-THC showed a greater behavioural activation compared to controls in response to challenge with Delta(9)-THC (150 microg/kg i.v.) and to challenge with morphine (0.5 mg/kg i.v.). Similar to that observed after repeated opiates, this behavioural sensitization was characterized by stereotyped activity. Animals administered with a schedule of morphine that induces behavioural sensitization to morphine also showed a behavioural sensitization to challenge with cannabinoids (Delta(9)-HC and WIN55212-2, 75 and 150 microg/kg i.v.). The effect of the challenge with Delta(9)-THC was prevented by the administration of the CB1 antagonist SR141716A (1 mg/kg i.p.), 40 min beforehand., Conclusions: The results of the present study demonstrate that repeated exposure to Delta(9)-THC induces behavioural sensitization not only to cannabinoids but also to opiates. This cross-sensitization was symmetrical since rats behaviourally sensitized to morphine were also sensitized to cannabinoids. These observations further support the evidence of an interaction between the opioid and the cannabinoid system and might provide a neurobiological basis for a relationship between cannabis use and opiate abuse.

The effect of chronic administration of desipramine or fluoxetine (10 mg/kg IP once a day for 2 weeks) on extracellular noradrenaline; serotonin and dopamine in the rat prefrontal cortex was studied by transcerebral microdialysis. Chronic desipramine increased extracellular noradrenaline and dopamine by three-fold as compared to saline controls. Acute challenge with 10 mg/kg desipramine increased by more than three-fold extracellular noradrenaline and dopamine in saline controls, but failed further to increase extracellular noradrenaline and dopamine in rats chronically administered desipramine. Chronic fluoxetine more than doubled the extracellular concentrations of serotonin but failed to change the extracellular concentrations of dopamine as compared to saline controls. Challenge with 5 mg/kg fluoxetine while almost doubling extracellular serotonin and dopamine concentrations in saline controls, failed further to increase extracellular serotonin and did not change extracellular dopamine in rats chronically exposed to fluoxetine. In contrast, challenge with 10 mg/kg desipramine normally increased extracellular dopamine in rats chronically exposed to fluoxetine. Therefore, chronic fluoxetine is associated with normal presynaptic dopamine transmission in the prefrontal cortex as a result of tolerance to fluoxetine-induced increase of extracellular dopamine; in contrast, chronic desipramine is associated with an increase of pre-synaptic dopamine transmission in the prefrontal cortex up to a level that cannot be further elevated by acute desipramine challenge. The results suggest that prefrontal cortex dopamine plays a different role in the antidepressant properties of desipramine and fluoxetine.

The atypical antidepressant mianserin, administered at doses of 1, 5 and 10 mg/kg SC, dose-dependently increased up to about 6 times extracellular dopamine in the medial prefrontal cortex of the rat, as estimated by vertical concentric microdialysis probes. Mianserin failed to modify extracellular dopamine in the nucleus accumbens. Mianserin also dose-dependently increased extracellular noradrenaline in the prefrontal cortex. Yohimbine, an alpha2 antagonist, increased extracellular dopamine in the prefrontal cortex but the maximal increase was lower than that elicited by mianserin. Yohimbine also increased extracellular noradrenaline in the prefrontal cortex, but to a lesser extent than dopamine. Clonidine, an alpha2 antagonist, decreased extracellular dopamine and noradrenaline in the prefrontal cortex but failed to affect extracellular dopamine in the nucleus accumbens. Ritanserin, a 5HT2 antagonist, at doses of 1.0 mg/kg, failed to increase extracellular dopamine in the prefrontal cortex, but significantly potentiated the increase in extracellular noradrenaline due to yohimbine. Ritanserin failed to potentiate the increase in extracellular noradrenaline elicited by yohimbine in the prefrontal cortex. The results are interpreted to indicate that mianserin increases extracellular DA as a result of the concurrent blockade of alpha2 and 5HT2 receptors. Failure to affect extracellular dopamine in the nucleus accumbens is explained as due to the lack of a significant effect of alpha2 and 5HT2 tone on DA release in the nucleus accumbens as compared to the prefrontal cortex. The results are consistent with the postulated relationship between antidepressant drug action and the ability to increase extracellular dopamine in the prefrontal cortex.

A single dose of the D1 agonist SKF 38393 (3 mg/kg) produces contralateral turning in unilaterally 6-hydroxydopamine lesioned rats only after a previous exposure of the animals to a dopamine agonist. This priming phenomenon is here investigated by studying the phosphorylation of DARPP-32, a dopamine- and cyclic AMP-regulated phosphoprotein functionally linked to D1 receptors in striatum. Dephospho-form of DARPP-32 in striatal tissue was measured by a back-phosphorylation assay. While the levels of DARPP-32 protein, as measured by quantitative immunoblotting, remained unchanged, a significant decrease of dephospho-DARPP-32 was observed in the denervated striatum of primed rats, indicating an increased phosphorylation in vivo of DARPP-32 in response to the D1 agonist. This study shows that an alteration of the dopamine-dependent signal transduction is related to the behavioral response to dopamine agents, suggesting a possible mechanism involved in the effects of these drugs in parkinsonian patients.

Drugs differing in their primary mechanism of action but having in common the ability to act as antidepressants such as fluoxetine (10 mg/kg SC), clomipramine (10 mg/kg IP), imipramine (10 mg/kg IP), desipramine (10 mg/kg IP) and (+/-) 8-OHDPAT (0.03 mg/kg SC) increase extracellular concentrations of dopamine in the rat prefrontal cortex but not in the medial nucleus accumbens. Buspirone (1 mg/kg SC) increased dopamine both in the prefrontal cortex and in the nucleus accumbens. Extracellular 5HT was increased by fluoxetine, clomipramine and imipramine but not by desipramine while 8-OHDPAT and buspirone decreased it. These results raise the possibility that the property of stimulating dopamine transmission in the prefrontal cortex has a role in the antidepressant properties of these drugs.

Concentric dialysis probes were vertically implanted in rats in the nucleus accumbens (Acc) of one side and in the dorsal caudate-putamen (CPu) of the other side. On the day after the implant the output of dopamine was monitored and the changes elicited by d-amphetamine sulphate were compared in the two areas. Amphetamine preferentially stimulated dopamine release in the Acc in a wide range of doses (0.25, 0.5, 1.0, 2.0 mg/kg SC) when Acc probes were located in the medial aspect of the Acc. In contrast, no significant differences between the Acc and the dorsal CPu were obtained in response to amphetamine (0.5 mg/kg SC) when Acc probes were located about 0.7 mm lateral to the previous site. It is concluded that the preferential effect of amphetamine in the Acc is related to precise topographical boundaries. This in turn might be related to the existence of a sharp anatomical and functional heterogeneity within the Acc.