Antagonism of behavioral effects of cocaine by selective dopamine receptor blockers.

The cocaine-antagonist effects of SCH 39166, which selectively blocks D1 dopamine receptors, were compared with those of YM 09151-2, a selective D2 receptor blocker, and flupenthixol, a nonselective blocker of both dopamine receptor subtypes. Squirrel monkeys were studied under a fixed-interval schedule of stimulus-shock termination, and the effects of cumulative doses of cocaine were determined alone and after pretreatment with each dopamine receptor blocker. When administered alone, cocaine (0.01-1.78 mg/kg, IV) had biphasic effects on responding: intermediate doses increased response rate, whereas higher doses decreased response rate. The ED50 for cocaine (average does that produced a half-maximal increase in response rate) was 0.04 mg/kg. Pretreatment with SCH 39166 (0.03 and 0.1 mg/kg, IV) resulted in surmountable antagonism of both the rate-increasing and rate-decreasing effects of cocaine, the ED50 being increased by as much as 13-fold. Similar effects were observed after pretreatment with YM 09151-2 (0.001 and 0.003 mg/kg, IV) and flupenthixol (0.01 and 0.03 mg/kg, IV), which respectively produced up to a 13-fold and 32-fold increase in ED50. There also was evidence for reciprocal antagonism of the rate-decreasing effects of the three dopamine receptor blockers by cocaine. The results suggest a prominent role for D1 as well as D2 dopamine receptors in mediating the effects of cocaine on schedule-controlled behavior.