SEROTONERGIC MECHANISMS INVOLVED IN THE DISCRIMINATIVE STIMULUS, REINFORCING AND SUBJECTIVE EFFECTS OF COCAINE

The purpose of the present manuscript is to review the current status of the role of serotonin (5-hydroxytryptamine; 5-HT) systems in the st imulus and reinforcing properties of cocaine in non-humans and the sub jective effects of cocaine in humans. Review of the current literature suggests that general enhancement (via precursor administration) or d epletion of brain 5-HT content (via neurotoxin administration or trypt ophan depletion) impact the reinforcing effects of cocaine in non-huma ns and its subjective effects in humans. Selective 5-HT reuptake inhib itors (SSRIs) enhance the discriminability of cocaine and decrease coc aine self-administration in animals, although data to the contrary als o exist. Studies in humans suggest that SSRIs attenuate the subjective effects of cocaine in humans. Although few drugs with selectivity for 5-HT2 receptors have been studied systematically, a 5-HT2 agonist and several antagonists show some efficacy in enhancing and reducing, res pectively, the reinforcing effects of cocaine in non-humans. Limited d ata from humans suggest that a 5-HT2 antagonist may also decrease the subjective effects of cocaine; thus, 5-HT2 compounds deserve further a ttention. The majority of studies evaluating the 5-HT3 antagonists hav e reported negative results across all paradigms. In summary, while th e functional significance of 5-HT receptors has not been fully elucida ted, these data suggest that changes in serotonergic activity can modu late the effects of cocaine in both animals and humans under a variety of experimental conditions. One commonality among the studies with po sitive findings is that cocaine effects are only partially modified by 5-HT agents regardless of the direction of change.