DIFFERENTIAL MODULATION OF BEHAVIORAL-EFFECTS OF COCAINE BY LOW-AND HIGH-EFFICACY D-1 AGONISTS

Dopamine D-1 agonists differing in efficacy with respect to stimulatio n of adenylate cyclase activity and other in vitro and in vivo criteri a were evaluated for their capacity to modulate the behavioral effects of cocaine in squirrel monkeys. Monkeys were trained either to respon d on a fixed-ratio schedule in which lever pressing terminated a stimu lus associated with electric shock or to discriminate cocaine from veh icle using a two-lever drug-discrimination procedure. When administere d in combination with cocaine, D-1 agonists displaying relatively low efficacy (SKF 38393, SKF 75670) attenuated both the rate-altering effe cts of cocaine on fixed-ratio responding and the discriminative-stimul us effects of cocaine, resulting in overall rightward shifts of the co caine dose-response functions. Maximal attenuation of the behavioral e ffects of cocaine by the D-1 partial agonises was comparable to that p roduced by the D-1 antagonist SCH 39166. In contrast, D-1 agonists dis playing relatively high efficacy (SKF 81297, SKF 82958, SKF 83189) eit her had little effect on or accentuated the rate-altering and discrimi native-stimulus effects of cocaine. The results show that D-1 partial agonists can act as functional cocaine antagonists and may be viable c andidate medications for the management of cocaine addiction.