Received for publication January 31, 2007.
Revised March 7, 2007.
Accepted for publication March 8, 2007.

Modulation of Heroin and Cocaine Self-Administration by Dopamine D1- and D2-Like Receptor Agonists in Rhesus Monkeys

Abstract

Cocaine-heroin combinations ("speedballs") are commonly self-administered by polydrug abusers. Speedball self-administration may reflect in part an enhancement of the reinforcing effects of the drug combination compared to either drug alone. The present study investigated the degree to which the dopamine receptor system plays a role in cocaine-induced enhancement of heroin self-administration. In rhesus monkeys trained under a progressive-ratio (PR) schedule of i.v. drug injection, combining heroin with cocaine shifted the heroin dose-response function leftward, and isobolographic analysis indicated that the combined effects were dose-additive. Similarly, combining heroin with the D1-like receptor agonists SKF 81297 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine HCl) and SKF 82958 (6-chloro-N-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine) resulted in a leftward shift in the heroin dose-response function that was dose-additive. In contrast, combining heroin with the D2-like agonists R(-)-propylnorapomorphine (NPA) and quinpirole shifted the heroin dose-response function to the right. Isobolographic analysis of the combined effects of heroin with NPA and quinpirole revealed infra-additive interactions in both cases. When combined with cocaine instead of heroin, both the D1-like receptor agonist SKF 81297 and the D2-like receptor agonist NPA enhanced cocaine self-administration. The combinations of SKF 81297 with cocaine were dose additive; however, the NPA-cocaine interaction was infra-additive. Taken together, the results suggest that D1- and D2-like receptor mechanisms may play qualitatively different roles in the combined self-administration of heroin and cocaine. In particular, stimulation of D1-like receptors enhances self-administration of heroin or cocaine individually, similar to the effects of combining cocaine with heroin, whereas stimulation of D2-like receptors appears to play primarily an inhibitory role.

Key words: cocaine, dopamine receptor, heroin, rhesus monkey, self-administration, speedball