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 cocaine. However, the specific receptors underlying this phenomenon have not been identified. To evaluate the role of the 5-HT1B receptor in mediating the 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 GR127935. GR127935 attenuated the ability of cocaine to stimulate locomotion and induce c-fos expression in the striatum. However, GR127935 had no apparent effect on the rewarding or sensitizing effects of cocaine. In contrast, as demonstrated previously, the 5-HT1B receptor KO mice showed a heightened locomotor response to cocaine, as well as an increased propensity to self-administer cocaine. Thus, an acute pharmacological blockade of the 5-HT1B receptor decreases some effects of cocaine, while a constitutive genetic KO of the same receptor has opposite effects. These results suggest that compensatory 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 vulnerability to drug abuse rather than a classic pharmacological tool.