Tolerance to 3,4-methylenedioxymethamphetamine is associated with impaired serotonin release

Tolerance to the behavioural effects of 3,4-methylenedioxymethamphetamine (MDMA) following high dose exposure has been attributed to alterations in serotonergic systems. The present study aimed to determine whether decreased 5-HT release and/or 5-HT(2A/C) receptor desensitization might play a role in tolerance by measuring the response to selective ligands following MDMA exposure. To this end, the latency to nose poke and emerge from a hide box to an open field arena following administration of various ligands to MDMA pre-treated and control rats was measured. Acute exposure to MDMA (0.0-3.3 mg/kg), the 5-HT releasing stimulant fenfluramine (0.0-2.0 mg/kg) and the 5-HT(2) receptor agonist m-CPP (0.0-1.25 mg/kg) increased nose poke and emergence latency. Following administration of doses that produce 5-HT(2A) receptor-mediated behaviours, the 5-HT(2) receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane failed to alter nose poke and emergence latency, suggesting a limited role of this receptor subtype in these behaviours. Activation of 5-HT(2C) receptors was implicated in the behavioural response to both MDMA and m-CPP since the increased emergence latency was dose-dependently attenuated by pre-treatment with the selective 5-HT(2C) receptor antagonist RS102221 (0.0-1.0 mg/kg). Tolerance to the behavioural effect of MDMA and fenfluramine but not m-CPP was produced by prior exposure to MDMA (10 mg/kg administered at two-hour intervals, total 40 mg/kg), and tissue levels of 5-HT and 5-HIAA were decreased. These findings suggest that tolerance to the increased nose poke and emergence latency produced by MDMA is due to impaired 5-HT release.