Psychopharmacology (1991) 104:425-431 003331589100140V Psychopharmacology © Springer-Verlag 1991 Original investigations Interaction of haloperidol and SCH 23390 with cocaine and dopamine receptor subtype-selective agonists on schedule-controlled behavior of squirrel monkeys J.M. Witkin, C.W. Schindler, S.R. Tella, and S.R. Goldbcrg Preclinical Pharmacology Branch, NIDA Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224, USA Received February 22, 1990 / Final version December 17, 1990 Abstract. Involvement of D 1 and D2 dopamine receptors in the effects of cocaine on schedule-controlled behavior was evaluated in squirrel monkeys responding under a multiple fixed-interval 5-min, fixed-ratio 10 schedule (mult FI FR) of food delivery. Cocaine and the D2 agonist quinpirole increased responding under the FI at certain doses and disrupted the temporal patterning of behavior. Higher doses of these drugs decreased respond- ing. In contrast, the D1 agonist SKF 38393 was devoid of behavioral activity up to 10 mg/kg where response suppression was obtained without significant modifica- tion of the temporal distribution of responding. The D2 antagonist haloperidol (0.001-0.03 mg/kg) did not alter the behavioral effects of cocaine up to doses that had pronounced behavioral effects on their own. However, haloperidol attenuated the behavioral effects of quin- pirole. In contrast, the D1 antagonist SCH 23390 parti- ally attenuated the response rate-suppressant effects of cocaine without blocking cocaine-induced disruptions of temporal response patterning. SCH 23390 did not an- tagonize the behavioral effects of SKF 38393. These results suggest that independent stimulation of either D 1 or D2 receptors alone does not play a major role in the effects of cocaine on schedule-controlled behavior of squirrel monkeys. Key words" Cocaine - Dopamine receptor subtypes - Behavioral effects - Squirrel monkeys Evidence that blockade of dopamine reuptake (cf Heik- kila et al. 1975) may be related to important behavioral effects of cocaine has primarily derived from correlation- al studies (cf Ritz et al. 1987; Bergman et al. 1989; Spealman et al. 1989). Direct experimental support for this idea contains inconsistencies that have not been satisfactorily resolved (see below). However, the discov- Offprint requests to: J.M. Witkin ery of multiple dopamine receptor subtypes in the central nervous system (cf Kebabian and Calne 1979; Clark and White 1987) and compounds which interact selectively with these sites (cf Waddington and O'Boyle 1989) has led to renewed experimental efforts to evaluate the role of dopamine in the behavioral effects of cocaine (cf Woolverton and Kleven 1988; Johanson and Fish- man 1989). Behavioral effects of cocaine are not consistently al- tered by selective dopamine antagonists. For example, the discriminative stimulus effects of cocaine have been reported to be only partially blocked by the D2 antago- nist haloperidol (Colpaert et al. 1978). Other reports have shown that D2 antagonists are either inactive or produce non-dose-related blockade of the discriminative stimulus effects of cocaine (Barrett and Appel 1989). Interpreta- tion of these results is further complicated since large, behaviorally-active doses of the antagonists are typically required for antagonist activity (cf Woods et al. 1987; Katz and Witkin 1991). Likewise, whereas the D1 antagonist SCH 23390 has been reported to block the discriminative stimulus effects of cocaine (Kleven et al. 1988), Barrett and Appel (1989) showed that antagonism was neither complete nor dose dependent. In addition to antagonism studies, a complimentary approach to the assessment of dopamine receptors in the behavioral effects of cocaine involves comparisons of selective dopamine receptor agonists with those of co- caine. For example, Barrett and Appel (1989) compared the effects of the D1 agonist SKF 38393, and the D2 agonist quinpirole with those of cocaine. In their study, rats were trained to discriminate 10 mg/kg cocaine from saline and subsequent tests were conducted by substitut- ing various doses of cocaine or the selective agonists. Whereas quinpirole and cocaine produced dose-depen- dent increases in responding on the cocaine-associated lever, SKF 38393 produced only saline-appropriate re- sponding. In squirrel monkeys, antagonism of behavioral and cardiovascular effects of cocaine by haloperidol or SCH 23390 have also been limited in extent and selec-