Effects of selective dopamine D3 receptor compounds in nonhuman primate models of cocaine and methamphetamine abuse (661.8)

Within the dopaminergic system, the D 3 R has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. The present studies examined the effects of D 3 ‐selective partial agonists and D 3 /D 2 R antagonists in three models of cocaine and MA abuse in rhesus monkeys. The highly selective D 3 partial agonist PG619 and the D 3 /D 2 R antagonists buspirone and eticlopride were administered chronically to monkeys self‐administering cocaine and MA (n=3/group) under a food‐drug choice procedure in which complete cocaine and MA dose‐response curves were determined each session. Neither PG 619 (0.1‐3.0 mg/kg, i.v.), buspirone (0.01‐0.3 mg/kg, i.m.) nor eticlopride (0.001‐0.01 mg/kg, i.v.) significantly decreased cocaine or MA choice and intake while buspirone significantly increased the choice of low drug doses. The ability of buspirone to block reinstatement was also examined. Using the choice procedure in which saline was substituted for the self‐administered drug, buspirone (1.0‐1.7 mg/kg, p.o.) was found to block both cocaine‐ and MA‐induced reinstatement. In relation to this, buspirone (0.03‐0.3 mg/kg, i.m.) was also found to be effective in blocking cocaine and MA discrimination in a separate group of monkeys (n=3/group). Overall, these data indicate that while buspirone did not block the reinforcing effects of stimulants when studied under a food‐drug choice paradigm, it was effective in reducing reinstatement and in attenuating the discriminative stimulus effects of cocaine and MA, supporting a potential use for this compound in drug abuse treatment. DA012460 Grant Funding Source : Supported by DA012460