Behavioral effects of selected opiates and phencyclidine in the nondependent and cyclazocine-dependent rhesus monkey.

Tolerance to the behavioral effects of selected opiate compounds (cyclazocine, ketocyclazocine, naloxone and the stereoisomers of N-allylnormetazocine) and phencyclidine was evaluated using cumulative dosing procedures in rhesus monkeys responding under a fixed-ratio (FR) schedule of food presentation. Initially, the i.v. injection of graded doses of each drug in 8-min time-out periods preceding sequential FR periods decreased responding after each time-out in dose-related fashion. Subsequently, daily administration of up to 11 mg/kg of cyclazocine led to an approximately 16 to 32-fold rightward shift in the dose-effect curves for cyclazocine and ketocyclazocine and an approximately 4-fold rightward shift in the dose-effect curves for phencyclidine and (+)-N-allynormetazocine. In contrast, the dose-effect curves for naloxone and (-)-N-allynormetazocine were generally unchanged or shifted leftward. Termination of daily cyclazocine administration produced signs of withdrawal which disappeared over several days in all monkeys. These included emesis, frequent aggressive display and disruption of schedule-controlled performance. Present results suggest that the rate-decreasing effects of racemic cyclazocine involve mechanisms distinct from those mediating the rate-decreasing effects of naloxone or (-)-N-allynormetazocine. The differing degrees of cross-tolerance produced to the rate-decreasing effects of ketocyclazocine and of phencyclidine and (+)-N-allynormetazocine also suggest that the latter compounds produce behavioral effects to some extent through mechanisms distinct from those through which ketocyclazocine is effective.