| Drug craving is thought to play an important role in drug relapse. Two factors that contribute to craving are exposure to environmental stimuli that have become associated with procuring and taking a drug, referred to as drug cues, or sampling the drug itself. The extinction/reinstatement model was used in the present study to examine whether cue- and drug-elicited craving for cocaine involve dopamine D1 receptors. Animals were trained to self-administer cocaine, with light and tone cues paired with each infusion. Subsequently, animals underwent extinction wherein reinforcement was withheld. Responding in the absence of cocaine reinforcement is referred to as cocaine-seeking behavior and serves as the index of motivation for cocaine. During extinction, responding declined and was reinstated subsequently by cocaine priming injections or by presentation of the cocaine-paired cues, reflecting the incentive motivational effects of these stimuli. The first study demonstrated that both D1 receptor antagonist and agonist drugs attenuate cue and cocaine reinstatement, but likely via the different mechanisms of reinforcement blockade versus decreased motivation, respectively. Also, low doses of the agonist reinstated cocaine-seeking behavior, suggesting the agonist has motivational effects that could be problematic from a therapeutic perspective. The second study demonstrated that agonist and antagonist co-administration reverses the attenuation of cocaine-primed reinstatement, suggesting D1 receptor mediation. The attenuation of cue reinstatement was not reversed. Thus, it remains unclear whether effects on cue reinstatement are D1 receptor-mediated. The reinstatement effects were dissociated from motor effects, suggesting the former is not the result of behavioral disruption. The final study demonstrated that antagonist infusion directly into amygdaloid nuclei, the posterior caudate putamen/globus pallidus region of the basal ganglia (BG), or the somatosensory/insular cortex (CTX) attenuates cocaine-seeking behavior, with the central amygdala and CTX infusions particularly sensitive to attenuating the reinforcing and/or motivating effects of cocaine, and the basolateral amygdala, BG, and CTX infusions particularly sensitive to attenuating cue effects. Collectively, these findings suggest that different populations of D1 receptors in divergent neural pathways process the motivational effects of cocaine versus cocaine-paired cues. |
