, Volume 101, Issue 1, pp 142-145

Antagonism of behavioral effects of cocaine by selective dopamine receptor blockers

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Abstract

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.

Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and of the “Guide for Care and Use of Laboratory Animals” of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education and Welfare, Publication No. (NIH)85-23, revised 1985