Modulation of the effects of cocaine by 5-HT1B receptors: a comparison of knockouts and antagonists

Serotonergic transmission has been suggested to modulate the effects of coc aine. However, the specific receptors underlying this phenomenon have not b een identified. To evaluate the role of the 5-HT1B receptor in mediating th e actions of cocaine, we used two model systems: knockout (KO) mice lacking the 5-HT1B receptor and an acute treatment with the 5-HT1B/1D antagonist G R127935. GR127935 attenuated the ability of cocaine to stimulate locomotion and induce c-fos expression in the striatum. However, GR127935 had no appa rent effect on the rewarding or sensitizing effects of cocaine. In contrast , as demonstrated previously, the 5-HT1B receptor KO mice showed a heighten ed locomotor response to cocaine, as well as an increased propensity to sel f-administer cocaine, Thus, an acute pharmacological blockade of the 5-HT1B receptor decreases some effects of cocaine, while a constitutive genetic K O of the same receptor has opposite effects. These results suggest that com pensatory changes have taken place during the development of the 5-HT1B KO mice, which may have rendered these mice more vulnerable to cocaine. The 5- HT1B KO mice should therefore be considered as a genetic model of vulnerabi lity to drug abuse rather than a classic pharmacological tool. (C) 2000 Els evier Science Inc. All rights reserved.