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.
Key wordsCocaine Behavioral effects Antagonism Dopamine receptors Squirrel monkeys
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- Barnett A, Iorio LC, Billard W (1986) Relationship of the behavioral effects of SCH 23390 and related benzazepines to their effects on dopamine1 (D1) receptors. In: Biggio G, Spano PF, Gessa GL (eds) Modulation of central and peripheral neurotransmitter function. Liviana Press, Padova, Italy, pp 15–25Google Scholar
- Barrett RL, Appel JB (1989) Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine. Psychopharmacology 99:13–16Google Scholar
- Herd JA, Morse WH, Kelleher RT, Jones LG (1969) Arterial hypertension in the squirrel monkey during behavioral experiments. Am J Physiol 27:24–29Google Scholar
- Kleven MS, Anthony EW, Goldberg LI, Woolverton WL (1988) Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D1 dopamine antagonist SCH 23390. Psychopharmacology 95:427–429Google Scholar
- Møller-Nielson I, Pederson V, Nymark M, Franck KF, Boeck V, Fjalland B, Christensen AV (1973) The comparative pharmacology of flupenthixol and some reference neuroleptics. Acta Pharmacol Toxicol 33:353–362Google Scholar
- Scheel-Krüger J, Braestrup C, Nielson M, Golembiowska K, Mogilnicka E (1977) Cocaine: discussion of the role of dopamine in the biochemical mechanism of action. In: Ellinwood EJ, Kilbey MM (eds) Cocaine and other stimulants. Plenum Press, New York, pp 373–407Google Scholar
- Woolverton WL, Kleven MS (1988) Multiple dopamine receptors and the behavioral effects of cocaine. In: Clouet D, Asghar K, Brown R (eds) Mechanisms of cocaine abuse and toxicity. NIDA research monograph 88. US Government Printing Office, Washington DC, pp 160–184Google Scholar
- Woolverton WL, Virus RM (1989) The effects of a D1 and a D2 dopamine antagonist on behavior maintained by cocaine or food. Pharmacol Biochem Behav 32:691–697Google Scholar