Differential Contributions of Dopamine D1, D2, and D3 Receptors to MDMA-Induced Effects on Locomotor Behavior Patterns in Mice

Abstract

MDMA or 'ecstasy' (3,4-methylenedioxymethamphetamine) is a commonly used psychoactive drug that has unusual and distinctive behavioral effects in both humans and animals. In rodents, MDMA administration produces a unique locomotor activity pattern, with high activity characterized by smooth locomotor paths and perseverative thigmotaxis. Although considerable evidence supports a major role for serotonin release in MDMA-induced locomotor activity, dopamine (DA) receptor antagonists have recently been shown to attenuate these effects. Here, we tested the hypothesis that DA D1, D2, and D3 receptors contribute to MDMA-induced alterations in locomotor activity and motor patterns. DA D1, D2, or D3 receptor knockout (KO) and wild-type (WT) mice received vehicle or (+/-)-MDMA and were tested for 60 min in the behavioral pattern monitor (BPM). D1 KO mice exhibited significant increases in MDMA-induced hyperactivity in the late testing phase as well as an overall increase in straight path movements. In contrast, D2 KO mice exhibited reductions in MDMA-induced hyperactivity in the late testing phase, and exhibited significantly less sensitivity to MDMA-induced perseverative thigmotaxis. At baseline, D2 KO mice also exhibited reduced activity and more circumscribed movements compared to WT mice. Female D3 KO mice showed a slight reduction in MDMA-induced hyperactivity. These results confirm differential modulatory roles for D1 and D2 and perhaps D3 receptors in MDMA-induced hyperactivity. More specifically, D1 receptor activation appears to modify the type of activity (linear vs circumscribed), whereas D2 receptor activation appears to contribute to the repetitive circling behavior produced by MDMA.