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Rationale +/- 3,4-Methylenedioxymethamphetamine (MDMA) produces effects on a number of neurochemical systems. Many studies have shown that repeated MDMA administration produces deficits in central serotonergic neurotransmission, which have been suggested to underlie some of the behavioural changes associated with use. Objectives The present studies sought to evaluate the functional statuses of the serotonin transporter (SERT) and the serotonin2c (5-HT2c) and serotonin2a (5-HT2a) receptors following treatment with MDMA to determine whether behavioural deficits could be attributed to alterations in these proteins. Methods Rats received a pretreatment regimen of MDMA (4 x 10mg/kg MDMA injections administered at 2h intervals) or the saline vehicle and, 2 weeks later, [3H] paroxetine binding was undertaken to assess densities of SERT. In other groups, dose-effect curves for MDMA-produced hyperactivity were determined. Additional groups were tested following a 12-week withdrawal period from MDMA in order to assess whether there was recovery of function. The functional status of the SERT was further examined by determining the effect of MDMA pretreatment on the reduction in MDMA-produced hyperactivity (0.0 - 10.0mg/kg) produced by the selective serotonin reuptake inhibitor, clomipramine (0.0 - 5.0mg/kg). The ability for the 5-HT2c receptor agonist, m-CPP (0.0 - 2.5mg/kg) to produce hypolocomotion or increased emergence latency or for the 5-HT2a receptor agonist, DOI (0.0 -  2.0mg/kg) to produce wetdog shakes (WDS) were examined in MDMA pretreated rats. The ability for the 5-HT2c receptors to modulate MDMA-produced hyperactivity was assessed by examining the effect of MDMA pretreatment on the potentiation of MDMA-produced hyperactivity produced by the selective antagonist, RS102221 (0.0 - 1.0mg/kg). Conversely, the modulatory abilities of the 5-HT2a receptors were assessed by examining the effect of MDMA pretreatment on the attenuation of MDMA-produced hyperactivity produced by the antagonist, ritanserin (0.0 - 10.0mg/kg). Results MDMA pretreatment produced widespread reductions in SERT binding densities 2 weeks following administration. Prior exposure to MDMA rendered rats tolerant to MDMA-produced hyperactivity when tested 2, but not 12, weeks following MDMA administration. Two weeks following MDMA pretreatment rats were also less responsive to the clomipramine-produced attenuation of MDMA-produced hyperactivity. MDMA pretreatment failed to alter M-CPP -produced hypolocomotion or increased emergence latency, but decreased the ability for DOI to induce WDS. Further, MDMA pretreated rats exhibited tolerance to RS102221 as shown by a rightward shift in the dose effect curve and complete tolerance to ritanserin. Conclusions Following MDMA pretreatment, the decreased SERT binding densities and inability of clomipramine to attenuate MDMA-produced effects might explain tolerance to the locomotor activating effects produced by MDMA. Functional recovery also occurred with extended abstinence from the drug, suggesting that MDMA produced transient serotonergic alterations. The results support the idea that the 5-HT2a and 5-HT2c receptors that modulate MDMA-produced hyperactivity are functionally distinct from the receptors that mediate m-CPP- and DOI-induced behavioural responses, as m-CPP-produced behaviours were resilient, yet RS102221-induced effects were reduced, by MDMA pretreatment. RS102221 is highly selective in comparison to ritanserin, yet there was only one dose that produced significant potentiation of MDMA-produced hyperactivity, whereas there were several effective ritanserin doses. This suggests that the 5-HT2a receptors had a greater role in modulating MDMA-produced hyperactivity. Additionally, 5-HT2a receptors might be more susceptible to MDMA-induced desensitisation than 5-HT2c receptors, as MDMA pretreated rats exhibited some tolerance to the potentiating effects of RS102221 but were unresponsive to any ritanserin dose. In conclusion, MDMA-induced locomotor tolerance was attributable to decreased SERT densities and function as well as desensitisation of 5-HT2a receptors that facilitate hyperactivity.

A Behavioural Analysis of Serotonergic Functional Status Following MDMA Exposure