The present study investigated the effects of priming with dopamine D1 and D3 agonists on the reinstatement extinguished cocaine-seeking behavior. Using a nonhuman primate model of relapse, squirrel monkeys were trained to self-administer cocaine under a second-order schedule of i.v. injection. Completion of every tenth response during a 10-min fixed interval produced a brief visual stimulus. The first FR 10 completed after the 10-min fixed interval produced a brief visual stimulus. The first FR 10 completed after the 10-min FI elapsed produced both the brief stimulus and an injection of cocaine. High rates of responding (0.8-2.0 resp/sec) were maintained under these conditions by 0.1 or 0.3 mg/kg/injection cocaine. Responding was subsequently reduced or eliminated during a series of extinction sessions in which saline was substituted for cocaine and the brief stimulus was omitted. Following extinction, responding could be reinstated robustly by administering a priming (noncontingent) injection of cocaine before the session and by reintroducing the cocaine-paired stimulus. D2-like agonists including NPA, apomorphine and to a lesser extent 7-OH-DPAT partially mimicked the priming effects of cocaine when tested alone and greatly accentuated the effects of cocaine when the drugs were studied in combination. In contrast, D1-like agonists and partial agonists including SKF 82959, SKF 81297 and SKF 38393 did not mimic the priming effects of cocaine, and instead, suppressed cocaine-induced reinstatement of responding. The selective D3 agonist PD 128,907 neither mimicked nor modulated the priming effects of cocaine. The results suggest a prominent role for D2 receptor mechanism in priming-induced relapse. Neither the D1 agonists SKF 81297 and SKF 82958 nor the D3 agonist PD 128907 reinstated cocaine-seeking behavior at doses that have been found to mimic the discriminative suppressed cocaine-induced reinstatement of drug-seeking, usually at doses that also suppress schedule-controlled behavior maintained by non-drug reinforcers. Pretreatment with PD 128907 did not attenuate cocaine-induced reinstatement at any dose tested. The results suggest that pharmacotherapies for cocaine addiction that target D1 or D3 receptors may be devoid of cocaine-like priming effects. The capacity of D1 agonists to attenuate cocaine-induced reinstatement of drug-seeking warrants further investigation.
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