The conditioning of the pharmacological actions of cocaine with environmental stimuli is thought to be a critical factor in the longterm addictive potential of this drug. Cocaine-related stimuli may increase the likelihood of relapse by evoking drug craving, and brain-imaging studies have identified the amygdala and nucleus accumbens (NAcc) as putative neuroanatomical substrates for these effects of cocaine cues. To study the significance of environmental stimuli in the recovery of extinguished cocaine-seeking behavior, male Wistar rats were trained to associate discriminative stimuli (S⌬s) with response-contingent availability of intravenous cocaine vs. saline. The rats then were subjected to repeated extinction sessions during which cocaine, saline, and the respective S⌬s were withheld until the animals reached an extinction criterion of <4 responses over three consecutive sessions. Subsequent re-exposure to the cocaine S⌬, but not the nonreward S⌬, produced strong recovery of responding at the previously active lever in the absence of any further drug availability. The efficacy and behavioral selectivity of the cocaine S⌬ remained unaltered throughout an 8-day test period. Exposure to the cocaine S⌬ significantly increased dopamine efflux in the NAcc and amygdala as measured by intracranial microdialysis in a separate group of rats. Dopamine levels remained unaltered in the presence of the nonreward S⌬. The results demonstrate that cocaine-predictive stimuli elicit robust and persistent cocaine-seeking behavior, and that this effect may involve activation of dopamine transmission in the NAcc and amygdala.T he classical conditioning of the pharmacological actions of cocaine with environmental stimuli is thought to have an important role in the long-term addictive potential of this drug. Environmental cues repeatedly associated with the subjective effects of cocaine can elicit drug craving (1-6) and possibly, automatic behavioral responses (7,8) that may lead to relapse in recovering cocaine addicts. Whereas the role of drug-related stimuli in motivating the resumption of drug use is not fully understood, such learned responses may be among the most important factors responsible for the high rates of relapse associated with cocaine and other drug addiction (9).Consistent with the well-established conditioned reactivity to cocaine cues in humans, classically conditioned behavioral responses to cocaine can be readily elicited in animals (10-14). However, it has been more difficult to demonstrate motivating effects of stimuli conditioned to cocaine in animal models of relapse. Stimuli paired contiguously with cocaine infusions in self-administering rats can reinstate responding following extinction (15-17), but these stimuli often produce only weak and transient effects (16,17), or fail to elicit cocaine-seeking behavior (18,19). The lack of robust and enduring behavioral effects of cocaine cues in many ''reinstatement'' studies appears inconsistent with the presumed strength and persistence of the motivating effe...

Anomalies in prefrontal cortex (PFC) function are posited to underpin difficulties in learning to suppress drug-seeking behavior during abstinence. As Group1 metabotropic glutamate receptors (mGluRs) regulate drug-related learning, we assayed the consequences of extended access to intravenous cocaine (6 hrs/day; 0.25 mg/infusion for 10 days) upon the PFC expression of Group1 mGluRs and the relevance of observed changes for cocaine-seeking. Following protracted withdrawal, cocaine-experienced animals exhibited a time-dependent intensification of cue-induced cocaine-seeking behavior and an impaired extinction of this behavior. These behavioral phenomena were associated with a time-dependent reduction in mGluR1/5 expression within ventromedial PFC (vmPFC) of cocaine-experienced animals exposed to extinction testing, but not in untested ones. Interestingly, pharmacological manipulations of vmPFC mGluR1/5 produced no immediate effects upon cue-induced cocaine-seeking behavior, but produced residual effects on a subsequent test for cocaine-seeking. At 3 days withdrawal, cocaine-experienced rats infused intra-vmPFC with mGluR1/5 antagonists, either before or after an initial test for cocaine-seeking, persisted in their cocaine-seeking akin to cocaine-experienced rats in protracted withdrawal. Conversely, cocaine-experienced rats infused with an mGluR1/5 agonist before the initial test for cocaine-seeking at 30 days withdrawal exhibited a facilitation of extinction learning. These data indicate that cue-elicited deficits in vmPFC Group1 mGluR function mediate resistance to extinction during protracted withdrawal from a history of extensive cocaine self-administration and pose pharmacological stimulation of these receptors as a potential approach to facilitate learned suppression of drug-seeking behavior which may aid drug abstinence.

Human cocaine addicts show altered function within the basal ganglia and the medial prefrontal cortex (mPFC) and altered glutamate function within these areas is postulated to be critical for cocaine addiction. The present project utilized a highly valid animal model of cocaine addiction, to test whether excessive use of cocaine alters glutamate function within these brain areas. Rats were trained to lever-press for IV saline vehicle or cocaine (0.25 mg/infusion) over seven 1-hr daily sessions, after which, saline controls and half of cocaine self-administering animals (brief access condition) received 10 more 1-hr daily sessions, while the remaining cocaine animals received 10 additional 6-hrs daily sessions (extended access condition). One, 14, or 60 days after the last selfadministration session, animals were sacrificed. Tissue samples from the ventral tegmental area (VTA), nucleus accumbens (N.Acc) core and shell, and mPFC were analyzed by immunoblotting for expression of Homer1b/c, Homer2a/b, mGluR1, mGluR5, NR2a, and NR2b subunits of the NMDA receptor. Brief and extended access to cocaine failed to alter protein levels within the VTA, and produced transient and similar changes in N.Acc protein expression, which were more pronounced in the core subregion. In contrast, extended access to cocaine resulted in distinct and long lasting alterations of protein expression within the mPFC that included: increased levels of Homer1b/c at 1 day, NR2b at 14 days, and NR2a at 60 days, of withdrawal. These data support the notion that altered NMDA function within the mPFC may contribute, in part, to the transition to excessive uncontrolled consumption of cocaine.

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