5-HYDROXYTRYPTAMINE(1B) RECEPTORS MODULATE THE EFFECT OF COCAINE ON C-FOS EXPRESSION - CONVERGING EVIDENCE USING 5-HYDROXYTRYPTAMINE(1B) KNOCKOUT MICE AND THE 5-HYDROXYTRYPTAMINE(1B 1D) ANTAGONIST GR127935/

Serotonergic transmission has been suggested to modulate the effects o f cocaine. However, the specific receptors and brain structures underl ying this phenomenon have not been identified, To test the possible co ntribution of the 5-hydroxytryptamine(1B) (5-HT1B) receptor, we studie d the induction of the immediate-early gene c-fos elicited by cocaine in knockout mice lacking this receptor. 5-HT1B knockout mice display a markedly reduced effect of cocaine on c-fos induction in different br ain structures, most notably in the striatum. In addition, the adminis tration to wild-type mice of the 5-HT1B receptor agonist RU24969 resul ts in a striatal induction of c-fos expression very similar to that in duced by cocaine in its time course, cellular and anatomical distribut ion, and pharmacology. Here, we also report the ability of a 5-HT1D re ceptor antagonist, GR127935, to antagonize 5-HT1D receptors in vivo. F inally, when administered to wild-type mice, GR127935 reduces the incr ease in striatal c-fos expression elicited by cocaine, These convergin g lines of evidence obtained with the knockout mice and 5-HT1B/1D anta gonist indicate that cocaine acts as an indirect agonist of 5-HT1B rec eptors in vivo and demonstrate that activation of 5-HT1B receptors con tributes to the cellular responses elicited by cocaine.