Requisite role of dorsal raphé in contextual cocaine-memory reconsolidation.

Memory reconsolidation is a process by which labile drug memories are restabilized in long-term memory stores, permitting their enduring control over drug-seeking behaviors. In the present study, we investigated the involvement of the dorsal raphé nuclei (DRN) in cocaine-memory reconsolidation. Sprague-Dawley rats (male, female) were trained to self-administer cocaine in a distinct environmental context to establish contextual drug memories. They then received extinction training in a different context. Next, the rats were re-exposed to the cocaine-predictive context for 15 min to reactivate their cocaine memories or remained in their home cages (no-reactivation control). Memory reactivation was sufficient to increase c-Fos expression, an index of neuronal activation, in the DRN, but not in the median raphé nuclei, during reconsolidation, compared to no reactivation. To determine whether DRN neuronal activity was necessary for cocaine-memory reconsolidation, rats received intra-DRN baclofen plus muscimol (BM; GABAB/A agonists) or vehicle microinfusions immediately after or 6 h after a memory reactivation session conducted with or without lever access. The effects of DRN functional inactivation on long-term memory strength, as indicated by the magnitude of context-induced cocaine seeking, were assessed 72 h later. Intra-DRN BM treatment immediately after memory reactivation with or without lever access attenuated subsequent context-induced cocaine-seeking behavior, independent of sex. Conversely, BM treatment in the adjacent periaqueductal gray (PAG) immediately after memory reactivation, or BM treatment in the DRN 6 h after memory reactivation, did not alter responding. Together, these findings indicate that the DRN plays a requisite role in maintaining cocaine-memory strength during reconsolidation.

Relapse to drug seeking following prolonged abstinence: the role of environmental stimuli.

Successful treatment of drug addiction must involve relapse prevention informed by our understanding of the neurobiological bases of drug relapse. In humans, exposure to drug-associated environmental stimuli can elicit drug craving and relapse. Because exposure to drug-paired stimuli similarly induces drug-seeking behavior in laboratory animals, several animal models of drug relapse have been developed. Here, we review animal models of cue-induced drug relapse and critically evaluate their validity and utility in addressing human relapse behaviors.

Role of glucocorticoid receptor-mediated mechanisms in cocaine memory enhancement.

The basolateral amygdala (BLA) is a critical site for the reconsolidation of labile contextual cocaine memories following retrieval-induced reactivation/destabilization. Here, we examined whether glucocorticoid receptors (GR), which are abundant in the BLA, mediate this phenomenon. Rats were trained to lever press for cocaine reinforcement in a distinct environmental context, followed by extinction training in a different context. Rats were then briefly exposed to the cocaine-paired context (to elicit memory reactivation and reconsolidation) or their home cages (no reactivation control). Exposure to the cocaine-paired context elicited greater serum corticosterone concentrations than home cage stay. Interestingly, the GR antagonist, mifepristone (3-10 ng/hemisphere), administered into the BLA after memory reactivation produced a further, dose-dependent increase in serum corticosterone concentrations during the putative time of cocaine-memory reconsolidation but produced an inverted U-shaped dose-effect curve on subsequent cocaine-seeking behavior 72 h later. This effect was anatomically selective, dependent on memory reactivation (i.e., not observed after home cage exposure), and did not reflect protracted hyperactivity. However, the effect was also observed when mifepristone was administered after novelty stress that mimics drug context-induced hypothalamic-pituitary-adrenal (HPA) axis activation without explicit memory reactivation. Together, these findings suggest that, similar to explicit memory retrieval, a stressful event is sufficient to destabilize cocaine memories and permit their manipulation. Furthermore, BLA GR stimulation exerts inhibitory feedback upon HPA axis activation and thus suppresses cocaine-memory reconsolidation.

Dopamine D1 or D2 receptor antagonism within the basolateral amygdala differentially alters the acquisition of cocaine-cue associations necessary for cue-induced reinstatement of cocaine-seeking.

The basolateral amygdala complex has been implicated in the formation and utilization of cocaine-cue associations in rat models of cue-induced reinstatement to cocaine-seeking behavior. We have previously demonstrated the importance of dopamine inputs to the basolateral amygdala complex in the reinstatement of cocaine-seeking behavior following chronic cocaine self-administration. Here we show that selective blockade of amygdalar dopamine D1 and D2 receptors during acquisition of cocaine-cue associations has distinctive effects on subsequent conditioned-cued cocaine-seeking behavior. Male, Sprague-Dawley rats were first trained to self-administer i.v. cocaine on a fixed ratio 1 schedule for 5 days. Subjects then received bilateral, intra-basolateral amygdala complex infusions of a dopamine D1 receptor antagonist (SCH23390, 0.25-2.0 microg/side; experiment 1), a dopamine D2 receptor antagonist (raclopride, 0.625-5.0 microg/side; experiment 2), or vehicle just prior to a single classical conditioning session, during which a light+tone cue was discretely paired with passive infusions of cocaine in the absence of lever responding. Following five additional days of cocaine self-administration and 7-10 days of extinction training, animals underwent multiple tests for cue-induced reinstatement. SCH23390 (2.0 microg/side), administered at the time of cocaine-cue association only, produced an attenuation of reinstatement to cue-induced cocaine-seeking behavior. In contrast, low doses of raclopride potentiated, while a higher dose of raclopride attenuated cue-induced reinstatement. These results demonstrate unique contributions of D1 vs. D2 receptors in mediating dopamine inputs within the basolateral amygdala complex during the formation of cocaine-stimulus associations that are critical for cue-induced reinstatement.

Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment.

To examine neuronal activation associated with incentive motivation for cocaine, cocaine-seeking behavior (operant responding without cocaine reinforcement) and Fos expression were examined in rats exposed to saline and cocaine priming injections and/or a self-administration environment. Rats were first trained to self-administer cocaine or received yoked saline administration ("control"). They then received 21 daily exposures to either the self-administration environment ("extinction") or a different environment ("no extinction") without cocaine available. Extinction training, used to decrease incentive motivation for cocaine elicited by the self-administration environment, decreased cocaine-seeking behavior elicited by both the environment and the cocaine priming injection. Exposure to the self-administration environment enhanced Fos expression in the no extinction group relative to control and extinction groups in the anterior cingulate, basolateral amygdala, hippocampal CA1 region, dentate gyrus, nucleus accumbens shell and core, and central gray area, regardless of whether or not priming injections were given. The priming injections enhanced Fos expression in the ventral tegmental area, caudate putamen, substantia nigra pars reticulata, entorhinal cortex, central amygdala, lateral amygdala, arcuate nucleus, and central gray area, regardless of group. Thus, these changes likely reflect an unconditioned effect from either cocaine or injection stress. The priming injections also enhanced Fos expression in the anterior cingulate, but only in cocaine-experienced groups, suggesting that this enhancement reflects an experience-dependent motivational effect of the priming injections. The results suggest that different neural circuits may be involved in the incentive motivational effects of cocaine-paired environmental stimuli versus priming injections and that the anterior cingulate may be part of a common pathway for both.

Dopamine overflow in the nucleus accumbens during extinction and reinstatement of cocaine self-administration behavior.

Both cocaine and cocaine-associated stimuli can reinstate extinguished self-administration behavior in animals. It has been suggested that reinstatement of drug-seeking behavior may be mediated by enhanced dopamine (DA) neurotransmission. To examine this hypothesis, DA overflow was measured in the nucleus accumbens (NAc) of rats during both extinction and cocaine-induced reinstatement of self-administration behavior. Rats were either allowed to self-administer cocaine for 3 hours daily for 14 days, or they received yoked administration of saline. A stimulus light above the lever was illuminated during drug delivery. Baseline DA overflow was measured in the NAc, using in vivo microdialysis 7 to 8 days after the last self-administration session. The rats were then placed into the operant chambers and allowed to respond in extinction for 90 minutes, during which responses resulted in presentation of the stimulus light. The rats then received a cocaine injection that reinstated self-administration behavior. Contrary to our hypothesis, cocaine-experienced animals exhibited less DA overflow in the NAc relative to controls during both extinction and reinstatement.

Time-dependent changes in cocaine-seeking behavior and extracellular dopamine levels in the amygdala during cocaine withdrawal.

Cocaine and cocaine-associated cues elicit craving in addicts and reinstate cocaine-seeking behavior in rats. Craving and cocaine-seeking behavior may be mediated by withdrawal-induced changes in dopamine (DA) neurotransmission in the amygdala. To examine whether there are concomittant changes in cocaine-seeking behavior and extracellular DA levels during withdrawal, experimental rats were trained to self-administer cocaine (0.75 mg/kg i.v.). After 14 daily 3-hour training sessions, animals underwent either a 1-day, 1-week, or 1-month withdrawal period. Extracellular DA levels were assessed during baseline, extinction, cue reinstatement, and cocaine (15 mg/kg i.p.) reinstatement of cocaine-seeking behavior (i.e., defined as the difference in nonreinforced lever presses on an active minus inactive lever). Cocaine-seeking behavior became more intense during the course of cocaine withdrawal. Additionally, basal and cocaine-induced extracellular DA levels were enhanced after the 1-month withdrawal period. We suggest that the former may reflect a persistent elevation in tonic extracellular DA levels in the amygdala, whereas the latter may reflect a persistent elevation in phasic extracellular DA levels.

Muscarinic receptor antagonism in the basolateral amygdala blocks acquisition of cocaine-stimulus association in a model of relapse to cocaine-seeking behavior in rats.

Recent evidence has demonstrated a critical role for the basolateral amygdala complex in the reinstatement of extinguished drug-seeking behavior produced by drug-paired cues. In the current study, we utilized a model of the acquisition and expression of cocaine-stimulus associative pairing in order to study the role of cholinergic input to the basolateral amygdala in mediating conditioned-cued reinstatement. Male, Sprague-Dawley rats were first trained daily to self-administer i.v. cocaine on a fixed ratio 1 schedule of reinforcement. The muscarinic acetylcholine receptor antagonist, scopolamine, was directly infused into the basolateral amygdala prior to: a) classically conditioned pairing of a tone+light stimulus with cocaine infusions (acquisition), or b) testing of conditioned-cued reinstatement following a period of withdrawal from cocaine and extinction of cocaine-paired lever responding. Infusion of scopolamine just prior to the classical conditioning trial produced a dose-dependent disruption of cocaine-seeking behavior maintained by cocaine-paired cues during the reinstatement test. In contrast, infusion of scopolamine prior to the reinstatement test had no effect on conditioned-cued reinstatement of cocaine-seeking behavior. These results indicate a crucial role for cholinergic innervation of muscarinic acetylcholine receptors in the basolateral amygdala during the formation, but not the expression, of stimulus-reward associations that mediate cue-induced cocaine-seeking behavior.

Predictive validity of the extinction/reinstatement model of drug craving.

The effects of chronic desmethylimipramine (DMI) treatment on measures of incentive motivation for cocaine were assessed in order to investigate the predictive validity of the extinction/reinstatement model of drug craving. Rats were trained to respond for cocaine infusions (0.75 mg/kg per 0.1 ml i.v.) or received yoked-saline infusions during daily 3-h sessions. A light and tone were presented with the infusions. Following self-administration training, each group received daily injections of either saline or DMI (10 mg/kg, i.p.) for 21 days of withdrawal from the self-administration regimen. On days 12-21 of withdrawal, rats were allowed to respond in the absence of cocaine reinforcement (extinction phase). After reaching an extinction criterion of no responses for 1 h, the cocaine-paired stimuli were repeatedly presented to reinstate responding (reinstatement phase). In the control group, DMI treatment did not alter responding during either test phase, but increased the response latency during the extinction phase. In contrast, DMI treatment in the cocaine group decreased responding and increased the response latency during both test phases, and decreased the extinction latency during the extinction phase. Overall, the effects of DMI were consistent with a reduction of incentive motivation for cocaine, lending support for the predictive validity of the extinction/reinstatement model of drug craving.

Differential effects of 7-OH-DPAT on amphetamine-induced stereotypy and conditioned place preference.

Low doses of the dopamine D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) produce a behavioral profile that is opposite to that produced by the psychomotor stimulants cocaine and amphetamine. For example, low doses of 7-OH-DPAT produce conditioned place aversion and hypolocomotion, whereas psychomotor stimulants produce conditioned place preference (CPP) and hyperlocomotion. In experiment 1, the effects of low doses of 7-OH-DPAT (0.01-0.1 mg/kg) on d-amphetamine-induced (1 mg/kg) motor behaviors and CPP were assessed. In experiment 2, the effects of 0.1 mg/kg 7-OH-DPAT on d-amphetamine (0-10 mg/kg) dose-response curves for the same behaviors were examined. During conditioning, drug injections were paired with a distinct compartment, whereas saline injections were paired with another compartment. Locomotion and headbobbing were measured following acute and repeated drug administration during conditioning and place conditioning was assessed 24 h following the last conditioning day. In experiment 1, d-amphetamine-induced locomotion was dose-dependently decreased by 7-OH-DPAT following repeated administration, which was probably due to the emergence of headbobbing, a behavior not observed with d-amphetamine alone. d-Amphetamine-CPP was not altered by co-administration of 0-0.03 mg/kg 7-OH-DPAT, but was attenuated by co-administration of 0.1 mg/kg 7-OH-DPAT. In experiment 2, 7-OH-DPAT co-administered with low doses of d-amphetamine (0-0.5 mg/kg) produced a decrease in locomotion following acute administration. However, 7-OH-DPAT produced sensitization of locomotion at the 0.5 mg/kg dose of d-amphetamine and an increase in headbobbing at the 0.5-10 mg/kg doses of d-amphetamine following repeated administration. In contrast, d-amphetamine-CPP was attenuated by co-administration of 7-OH-DPAT. These findings suggest that 0.1 mg/kg 7-OH-DPAT attenuates the reinforcing effects of d-amphetamine despite enhancing stereotypic behaviors.

Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats.

RATIONALE: Clinical studies examining the efficacy of the selective serotonin reuptake inhibitor, fluoxetine, in decreasing craving and cocaine use have been inconsistent. OBJECTIVE: To understand better the effects of fluoxetine treatment on incentive motivation for cocaine, the present study assessed the effects of chronic fluoxetine treatment on cocaine-seeking behavior in rats following exposure to a cocaine self-administration environment or a cocaine priming injection. METHODS: Rats were trained to press a lever for a cocaine reinforcer (0.5 mg/kg per 0.1 ml, i.v.) or received yoked administration of saline. They were then withdrawn from this regimen and given 20 daily injections of saline or fluoxetine (3.0 mg/kg, i.p.). Twenty-four hours after the last injection, the rats were placed in the self-administration environment and cocaine-seeking behavior (i.e., non-reinforced lever pressing) was measured for 90 min. Reinstatement of extinguished cocaine-seeking behavior was then measured for 60 min following a saline injection and for 90 min following a cocaine priming injection (15 mg/kg, i.p.). RESULTS: Chronic fluoxetine treatment attenuated cocaine-seeking behavior following exposure to the self-administration environment in most rats (n = 16), but enhanced cocaine-seeking behavior in two rats. Furthermore, the treatment failed to alter cocaine-seeking behavior following a cocaine priming injection. Interestingly, the amount of cocaine intake during self-administration training correlated with cocaine-seeking behavior following the cocaine priming injection. In fact, the priming injection reinstated cocaine-seeking behavior only in rats with high, but not low, cocaine intake based on a median split. CONCLUSIONS: These results suggest that chronic fluoxetine treatment decreases motivation for cocaine when animals are in a cocaine-free state. Furthermore, individual differences in cocaine use are related to individual differences in sensitivity to the incentive motivational effects of cocaine priming.

Behavioral interactions produced by co-administration of 7-OH-DPAT with cocaine or apomorphine in the rat.

Previous research from our laboratory suggests that low doses (<0.1 mg/kg) of the dopamine (DA) D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) attenuate conditioned place preference (CPP) produced by the indirect DA agonist d-amphetamine, but enhance d-amphetamine-induced stereotypic behaviors. This study further examined the effects of 7-OH-DPAT on behaviors produced by the indirect DA agonist, cocaine, and the non-selective direct DA agonist, apomorphine. To examine whether 7-OH-DPAT would alter cocaine and apomorphine dose-response curves for motor behaviors and CPP, 0.1 mg/kg 7-OH-DPAT was co-administered with 0-30 mg/kg cocaine and 0-3 mg/kg apomorphine. To establish place conditioning, drug injections were paired with one of two distinctly different compartments, whereas saline injections were paired with the other compartment. Locomotion, sniffing, oral stereotypy, and headbobbing were measured following acute and repeated drug administration during conditioning, and place conditioning was assessed 24 h following the last conditioning day. 7-OH-DPAT enhanced cocaine- and apomorphine-induced stereotypies following repeated administration. 7-OH-DPAT also attenuated cocaine-CPP, but potentiated apomorphine-CPP. Furthermore, 7-OH-DPAT attenuated locomotion produced by high doses of apomorphine. The attenuation of cocaine-CPP by 7-OH-DPAT likely involves stimulation of D2/D3 autoreceptors in the mesolimbic pathway, whereas the potentiation of apomorphine-CPP likely involves stimulation of D2/D3 postsynaptic receptors. Furthermore, it is suggested that attenuation of apomorphine-induced locomotion by 7-OH-DPAT likely involves stimulation of postsynaptic D3 receptors in the mesolimbic pathway. Thus, if postsynaptic D3 receptors are involved in mediating CPP and locomotion, then stimulation of D3 receptors may facilitate CPP but inhibit locomotion.

Sub-region specific contribution of the ventral hippocampus to drug context-induced reinstatement of cocaine-seeking behavior in rats.

The ventral hippocampus (VH) plays critical roles in cue-induced and cocaine-primed reinstatement of cocaine seeking [Rogers JL, See RE (2007) Neurobiol Learn Mem 87:688-692]. Subregions of the VH make distinct projections to elements of the brain relapse circuitry that mediate drug context-induced reinstatement. Thus, the VH may also critically contribute to this form of cocaine seeking in a subregion-specific manner. Accordingly, this study evaluated the hypothesis that functional inactivation of the ventral hippocampus proper (VHp)-but not of the dentate gyrus (DG)-impairs cocaine seeking elicited by re-exposure to a drug-paired environmental context. Rats were trained to lever press for un-signaled i.v. cocaine infusions (0.15 mg/infusion) in a distinct environmental context (cocaine-paired context) followed by extinction training in a distinctly different context (extinction context). Subsequently, cocaine-seeking behavior (i.e., non-reinforced active lever responding) was assessed in either the previously cocaine-paired context or the extinction context. Rats received bilateral microinfusions of the GABA agonist cocktail, baclofen+muscimol (BM: 1.0/.01 mM), or vehicle into the VHp, DG, or the posterior dorsal hippocampus (pDH; extra-VH control) immediately before each test session. Exposure to the previously cocaine-paired context, but not the extinction context, reinstated extinguished cocaine-seeking behavior following vehicle pretreatment. BM pretreatment administered into the VHp, but not the DG or pDH, significantly attenuated drug context-induced cocaine seeking. These results indicate that the VH contributes to drug context-induced cocaine seeking in a subregion-specific manner, with the functional integrity of the VHp being necessary for memory or motivational aspects of drug-paired environmental stimuli that sustain stimulus control over goal-directed behavior.

Effects of SCH-23390 on dopamine D1 receptor occupancy and locomotion produced by intraaccumbens cocaine infusion.

This study examined the effects of both systemic and intraaccumbens administration of SCH-23390 in rats on dopamine D1 receptor occupancy and on locomotor activity produced by intraaccumbens infusion of cocaine. In experiment 1, rats received SCH-23390 (0-1 mg/kg, i.p.) 15 minutes prior to intraaccumbens infusion of cocaine (0 or 100 microg/side). In experiment 2, rats received coinfusion of SCH-23390 (0-1 microg/side) and cocaine (0 or 100 microg/side) into the nucleus accumbens (NAc). After behavioral testing, receptors occupied by SCH-23390 were quantified by injecting animals with their respective dose of SCH-23390, followed by a systemic injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Receptors occupied by SCH-23390, and therefore protected from EEDQ-induced inactivation, were quantified from autoradiograms of sections labeled with 3H-SCH-23390. Systemic administration of SCH-23390 dose-dependently (0.1-1.0 mg/kg) reversed cocaine-induced locomotion and occupied 72-100% of D1-like receptors in the anterior NAc. D1 receptor occupancy following systemic administration of SCH-23390 was evident as an inverted U-shaped, dose-dependent change, with the greatest occupancy observed at the intermediate dose of 0.3 mg/kg. Intraaccumbens infusion of SCH-23390 did not alter cocaine-induced locomotor activity despite occupying 40-60% of D1-like receptors in the anterior NAc core and shell. The findings that systemic, but not intraaccumbens, administration of SCH-23390 potently reversed locomotion produced by intraaccumbens cocaine infusion suggest that stimulation of D1 receptors in regions other than the NAc is involved in locomotion produced by intraaccumbens infusion of cocaine, and that stimulation of D1 receptors in the NAc is not necessary for this behavior.

Effects of D3-preferring agonists 7-OH-PIPAT and PD-128,907 on motor behaviors and place conditioning.

Dose-dependent effects of 7-OH-PIPAT and PD-128,907 on motor behaviors and place conditioning were examined in rats. Four 2-day conditioning trials were conducted over 8 consecutive days. On one day of each trial, animals received an injection of either saline, one of six doses of 7-OH-PIPAT (0.01-10.0 mg/kg), or one of five doses of PD-128,907 (0.01-1.0 mg/kg), and were placed into a distinct compartment for 40 min. On the other day, animals received an injection of saline and were placed into a different compartment for 40 min. Locomotion, sniffing, and yawning were measured following the first and last drug injections. Place conditioning was assessed the day following the last conditioning trial. None of the doses of 7-OH-PIPAT or 0-0.3 mg/kg PD-128,907 produced place conditioning. However, 1 mg/kg PD-128,907 produced conditioned place preference (CPP). Across doses, both 7-OH-PIPAT and PD-128,907 produced a U-shaped change in sniffing and locomotion and an inverted U-shaped change in yawning. Across time, lower doses produced a decrease in sniffing and locomotion and an increase in yawning that were evident immediately, whereas higher doses produced a biphasic change in that there was an initial decrease followed by an increase in sniffing and locomotion. Behaviors produced by both low and high doses were sensitized following repeated administration. PD-128,907 produced CPP and was more potent than 7-OH-PIPAT in altering motor behaviors, possibly due to its greater selectivity for the D3 receptor.

Differential effects of intra-accumbens sulpiride on cocaine-induced locomotion and conditioned place preference.

The effects of intra-accumbens sulpiride on conditioned place preference and locomotion produced by i.v. cocaine were investigated. Every other day during conditioning, rats received infusions of sulpiride (0-0.4 microgram) into the nucleus accumbens (NAc) or caudate-putamen. Fifteen min later, they were placed into a distinct compartment and injected with saline or cocaine (4.2 mg/kg, i.v.). On the alternate days, rats received sham intracranial injections and were placed into a different compartment. Locomotion and stereotypies were assessed after the first and last injection, and conditioned place preference was assessed 24 hr after the last conditioning day. After behavioral testing, receptors occupied by sulpiride were quantified by injecting rats intracranially with their respective dose of sulpiride, followed by a systemic injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Receptors protected from EEDQ induced inactivation by sulpiride were revealed on autoradiograms of sections labeled with 3H-sulpiride. Sulpiride did not alter cocaine-conditioned place preference or cocaine-induced stereotypies. However, the two lowest doses of intra-accumbens sulpiride attenuated cocaine-induced locomotion and occupied > 42% of the sulpiride binding sites in the NAc, and the highest dose completely reversed cocaine-induced locomotion and occupied > 96% of the sulpiride binding sites in the NAc. Intracaudate sulpiride also attenuated cocaine-induced locomotion without occupying a significant number of binding sites in the NAc. These findings suggest that D2-like receptors in the NAc and anterior medial caudate-putamen are involved in cocaine-induced locomotion, but not cocaine-conditioned place preference.

Effects of intraaccumbens administration of SCH-23390 on cocaine-induced locomotion and conditioned place preference.

The effects of systemic (0-1.0 mg/kg) or intraaccumbens (0-1.0 microg/side) administration of SCH-23390 on cocaine-induced (0 or 4.2 mg/kg, i.v.) locomotion, sniffing, and conditioned place preference (CPP) were investigated in rats. After behavioral testing was completed, animals were injected with their respective dose of SCH-23390 into the nucleus accumbens (NAc), followed by a systemic injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Receptors occupied by intraaccumbens SCH-23390, and therefore protected from EEDQ-induced inactivation, were then quantified from autoradiograms of sections labeled with 3H-SCH-23390. Systemic administration of 0.5 and 1.0 mg/kg SCH-23390 reversed cocaine-induced locomotion, sniffing, and CPP, suggesting that stimulation of D1-like receptors is necessary for these behavioral changes. Intraaccumbens administration of 1.0 microg/side SCH-23390 reversed cocaine-CPP, and this dose occupied D1-like receptors primarily in the rostral pole of the NAc. Intraaccumbens administration of 0.5 microg/side SCH-23390 reversed cocaine-induced locomotion. However, this dose occupied a similar number of D1-like receptors in the NAc as a lower and behaviorally ineffective dose of 0.1 microg/side, but occupied more receptors in the caudate-putamen relative to both the 0.1 and 1.0 microg/side doses. These findings suggest that stimulation of D1-like receptors in the NAc is necessary for cocaine-CPP, but not for cocaine-induced locomotion.