Effect of ±3,4-methylenedioxymethamphetamine pre-treatment on Serotonin 2C receptor function

Abstract

Recreational use of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') has increased considerably in recent years. MDMA is a ring-substituted amphetamine derivative that produces increased synaptic levels of serotonin (5-HT) and dopamine (DA). MDMA induces hyperactivity in laboratory rats in a manner similar to other structurally related stimulant drugs. There is increasing evidence that administration of MDMA results in neurotoxicity. Specifically, MDMA has been shown to significantly decrease regional brain 5-HT content and to produce nerve terminal degeneration in rodent and primate brains. Serotonergic transmission changes induced by MDMA have been reported to cause altered function and density of 5-HT receptors. In the present study, the functional status of 5-HT 2C receptors in MDMA-exposed and control rats was compared by examining the effects of selective antagonists on locomotor activity. MDMA (10.0 mg/kg)-induced hyperactivity was potentiated by pre-treatment with the selective 5-HT 2C antagonists, RS102221 and SB200646. In order to determine whether MDMA pre-treatment altered these effects, rats were pretreated with MDMA (4 x 10.0 mg/kg MDMA at 2 hr intervals) or the saline vehicle 2 weeks prior to locomotor tests. 5-HT 2C receptor antagonists failed to potentiate MDMA-produced hyperactivity for rats that received pre-exposure to MDMA, suggesting a down-regulation of this receptor subtype.