Differential contributions of dopamine D1, D2, and D3 receptors to MDMA-induced effects on locomotor behavior patterns in mice

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 D-1, D-2, and D-3 receptors contribute to MDMA-induced alterations in locomotor activity and motor patterns. DA D-1, D-2, or D-3 receptor knockout ( KO) and wild-type ( WT) mice received vehicle or ( +/-)-MDMA and were tested for 60 min in the behavioral pattern monitor ( BPM). D-1 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, D-2 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, D-2 KO mice also exhibited reduced activity and more circumscribed movements compared to WT mice. Female D-3 KO mice showed a slight reduction in MDMA-induced hyperactivity. These results confirm differential modulatory roles for D-1 and D-2 and perhaps D-3 receptors in MDMA-induced hyperactivity. More specifically, D-1 receptor activation appears to modify the type of activity ( linear vs circumscribed), whereas D-2 receptor activation appears to contribute to the repetitive circling behavior produced by MDMA.