Effect of 5-HT depletion by MDMA on hyperthermia and Arc mRNA induction in rat brain.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) administration to rats produces an acute hyperthermic response and induces localised neuronal activation, which can be visualised via expression of immediate-early genes. The pharmacological and anatomical basis of these effects are unclear. At high doses, MDMA also causes selective neurotoxicity at serotonergic nerve terminals.
OBJECTIVE: We investigated the effect of 5-hydroxytryptamine (5-HT) depletion on the acute hyperthermic response to MDMA and the pattern of neuronal excitation indicated by Arc (activity-regulated cytoskeleton associated gene) in naive rats and following administration of MDMA at a neurotoxic dose.
METHODS: Expression of Arc mRNA was investigated by in situ hybridisation histochemistry using 35S-labelled oligonucleotide probe.
RESULTS: MDMA induced a significant hyperthermia together with increased Arc mRNA expression in cortical regions, caudate-putamen and CA1 hippocampus but not hypothalamus. At 21 days after a neurotoxic dose of MDMA, brain 5-HT and 5-HIAA levels were significantly reduced by 21-32%. In these animals, both the hyperthermic response and the pattern and extent of Arc mRNA expression induced by a subsequent dose of MDMA were unaltered. However, basal Arc expression was significantly increased in cortical regions and CA1 hippocampus.
CONCLUSION: We conclude that the acute hyperthermic response induced by MDMA is not attenuated by moderate depletion of 5-HT, further questioning mediation via a serotonergic mechanism. Arc mRNA induction by MDMA exhibits highly localised expression, which is not altered following 5-HT depletion. However, following a neurotoxic dose of MDMA, basal expression of Arc is increased, particularly in cortex and CA1, suggesting that mechanisms underlying synaptic plasticity might also be modified.