Abstract

Serotonergic transmission has been suggested to modulate the effects of cocaine. However, the specific receptors and brain structures underlying this phenomenon have not been identified. To test the possible contribution of the 5-hydroxytryptamine_1B(5-HT_1B) receptor, we studied the induction of the immediate-early gene c-fos elicited by cocaine in knockout mice lacking this receptor. 5-HT_1B knockout mice display a markedly reduced effect of cocaine on c-fosinduction in different brain structures, most notably in the striatum. In addition, the administration to wild-type mice of the 5-HT_1B receptor agonist RU24969 results in a striatal induction of c-fos expression very similar to that induced by cocaine in its time course, cellular and anatomical distribution, and pharmacology. Here, we also report the ability of a 5-HT_1D receptor antagonist, GR127935, to antagonize 5-HT_1B receptors in vivo. Finally, when administered to wild-type mice, GR127935 reduces the increase in striatal c-fos expression elicited by cocaine. These converging lines of evidence obtained with the knockout mice and 5-HT_1B/1D antagonist indicate that cocaine acts as an indirect agonist of 5-HT_1B receptors in vivoand demonstrate that activation of 5-HT_1B receptors contributes to the cellular responses elicited by cocaine.