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.

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 withdrawalinduced changes in dopamine (DA) Cocaine-seeking behavior; Cocaine withdrawal; Dopamine; Amygdala; Reinstatement; Extinction; Self-administration Craving is thought to play a critical role in drug relapse (Dackis and Gold 1985;Gawin and Kleber 1986;Wallace 1989). Gawin and Kleber (1986) have suggested that early during withdrawal from a cocaine binge there is little or no craving, and that later during withdrawal there is intense craving that can be exacerbated by cocaine-paired cues. In the laboratory, addicts exposed to drug-related cues (Childress et al. 1988;Ehrman et al. 1992;Satel et al. 1995) or given a cocaine priming injection report intense craving (Jaffe et al. 1989;Kosten et al. 1992;Preston et al. 1993) and exhibit conditioned physiological changes (Ehrman et al. 1992). Similarly, animals with a history of cocaine self-administration exhibit reinstatement of extinguished cocaine-seeking behavior after presentation of cocaine-paired cues or a cocaine priming injection (Davis and Smith 1976;Stewart 1984;Stewart et al. 1984). In these studies, cocaine-seeking behavior is measured as nonreinforced lever-pressing behavior.Reinstatement of cocaine-seeking behavior may be mediated by enhanced dopamine (DA) neurotransmission because systemic administration of indirect (Gerber and Stretch 1975;de Wit and Stewart 1981;Worley et al. 1994) or direct DA receptor agonists (de Wit and Stewart 1981;Wise et al. 1990;Self et al. 1996) reinstates cocaine-seeking behavior. It has been suggested based on localization studies that the nucleus accumbens (NAc) is involved because drugs that enhance DA neu- Received September 11, 1997; revised November 7, 1997; accepted November 13, 1997. N EUROPSYCHOPHARMACOLOGY 1998 -VOL . 19 , NO . 1 Cocaine-Seeking Behavior and Dopamine 49 rotransmission in this region reinstate cocaine-seeking behavior (Stewart 1984). Studies have also examined conditioned DA neurotransmission in the NAc after presentation of cocaine-paired cues, but the results have been controversial. After presentation of a light paired previously with cocaine self-administration, in vivo voltammetry studies have demonstrated that putative DA-related signals increase in the NAc (Gratton and Wise 1994;Kiyatkin and Stein 1994;Kiyatkin 1995), whereas an in vivo microdialysis study indicated no changes in extracellular DA levels (Neisewander et al. 1996). Electrophysiological studies have demonstrated a change in neuronal firing in the NAc prior to cocainereinforced lever pressing (Chang et al. 1994; Deadwyler 1994, 1996; Peoples and West 1996). This anticipatory response may be DA mediated in some (Carelli and Deadwyler 1996), but not all cells (Chang et al. 1994). Furthermore, Fontana et al. (1993) found a context-dependent sensitization of both locomotor behavior and extracellular DA levels in the NAc after a cocaine challenge ...

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.

Previous research suggests that cocaine dysregulates dopamine D 3 receptors. The present study examined the time course of changes in dopamine D 3 receptor binding after terminating a cocaine self-administration regimen.-tetralin was used to label dopamine D 3 receptors in rats that had undergone testing for cocaine-seeking behavior reinstated by a cocaine priming injection (15 mg/kg, i.p.; the behavior results have been previously published), and were killed 24 h after the test at time points that were either 2, 8, or 31-32 days after their last cocaine self-administration session. The results indicated a timedependent increase in D 3 receptor binding relative to controls that received saline yoked to the delivery of cocaine in an experimental animal. Specifically, there was no significant change in D 3 receptor binding in cocaine-experienced rats killed at the 2-or 8-day time points relative to controls, but there was an increase in D 3 receptor binding in the nucleus accumbens core and ventral caudate-putamen in rats killed at the 31-to 32-day time point. In a subsequent experiment, we replicated the increase in D 3 receptor binding in rats that underwent a less extensive self-administration regimen, then were tested for cocaine-primed reinstatement of cocaine-seeking behavior, and then were killed 24 h later at a time point of 22 days after their last self-administration session. Furthermore, the increase in binding was attenuated by repeated 7-hydroxy-N,N-di-n-propyl-2-aminotetralin administration (1 mg/kg/day, s.c. for 14 days), a regimen that also reduces cocaine-seeking behavior in animals when tested in a nondrug state. Collectively, the findings suggest that regulatory responses of D 3 receptors may be functionally related to changes in propensity for cocaine-seeking behavior.

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.