Locomotor response to MDMA is attenuated in knockout mice lacking the 5-HT1B receptor

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) is a psychoactive drug of abuse which is increasingly popular in human recreational drug use. In rats, the drug has been shown to stimulate locomotion while decreasing exploratory behavior. MDMA acts as an indirect agonist of serotonin (5-HT) receptors by inducing 5-HT release by a 5-HT reuptake transporter-dependent mechanism, although it is not known which 5-HT receptors are important for the behavioral effects of the drug. In order to examine the role of specific 5-HT receptors, we assessed the behavioral effects of MDMA on knockout mice lacking the 5-HT_1B receptor. Knockout animals show a reduced locomotor response to MDMA, although delayed locomotor stimulation is present in these animals. This finding indicates that the locomotor effects of MDMA are dependent upon the 5-HT_1B receptor, at least in part. In contrast, MDMA eliminates exploratory behavior in both normal and knockout mice, suggesting that the exploratory suppression induced by MDMA occurs through mechanisms other than activation of the 5-HT_1B receptor. To confirm these findings, we tested the effects of MDMA on the locomotor and exploratory behavior of wild-type mice pretreated with GR 127935, a 5-HT_1B/1D receptor antagonist. These mice had an attenuated locomotor response to MDMA, but still exhibited the drug-induced suppression of exploration.