3,4-Methylenedioxymethamphetamine (MDMA), an analog of the amphetamine class, is a psychostimulant and a popular drug of abuse. MDMA is considered to be selectively neurotoxic to serotonergic nerve terminals in different brain regions. Repeated exposure to MDMA during adolescence is neuroprotective against a subsequent neurotoxic regimen of MDMA in adulthood. This phenomenon is similar to ischemic preconditioning, where repeated exposure to sub-lethal insults results in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-toxic dose of MDMA in adult rats provides neuroprotection against subsequent MDMA induced 5-HT depletion and to evaluate the mechanisms involved. Preconditioning with MDMA (10 mg/kg i.p.) daily for 4 days provided significant protection against MDMA-induced 5-HT depletion in the striatum, hippocampus and cortex. Preconditioning with MDMA (10 mg/kg i.p.) daily for 4 days provided significant protection against methamphetamine (METH)-induced 5-HT, but not DA, depletion in the striatum. Since the neuroprotection is specific to the serotonergic neurons, it is possible that preconditioning with MDMA results in neuroadaptive changes in 5-HT containing neurons. The role for alterations in MDMA-induced hyperthermia and brain MDMA concentrations was ruled out.
Repeated exposure to Clozapine, at doses known to produce 5-HT2 receptor downregulation, provided significant protection against MDMA-induced 5-HT depletion in the striatum, hippocampus and cortex. However, it is inconclusive whether repeated exposure to MDMA results in downregulation of 5-HT2 receptor function and expression.
Repeated exposure to MDMA resulted in the downregulation of serotonin transporter (SERT) expression. Steady state 5-HT uptake in hippocampal synaptosomal preparations in rats previously exposed to MDMA was significantly reduced when compared to vehicle treated animals. SERT plays a key role in MDMA-induced 5-HT neurotoxicity and downregulation of SERT function after preconditioning with MDMA may contribute towards the neuroprotection.
Taken together, these studies suggest that repeated exposure to MDMA provides protection against a 5-HT depleting dose of MDMA and that downregulation of SERT function may contribute towards this neuroprotective phenomenon.