Differential effects of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") on BDNF mRNA expression in rat frontal...

The serotonergic neurotoxin 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") produces rapid serotonin (5-HT) depletion in different areas of the forebrain after acute administration to rats and other animal species. We previously found that 5-HT depletion induced by acute MDMA treatment was transient in the frontal cortex, but not in the hippocampus, and recovery of cortical 5-HT levels correlated with an induction of CRE-binding activity and increased expression of tryptophan-hydroxylase (TPH), the rate-limiting enzyme in 5-HT biosynthesis. As the brain-derived neurotrophic factor (BDNF) stimulates the growth and sprouting of serotonergic neurons, we sought the possible involvement of this neurotrophin in the region-specific increase in TPH mRNA expression induced by MDMA. We here report that, 24-48 h after acute MDMA treatment, the expression of BDNF in the frontal cortex is increased by approximately 33-70%, and the levels of the transcription factor phospho-CREB are also increased. In the hippocampus, however, a time-dependent decrease in BDNF mRNA expression (maximal decrease of approximately 73%) is found in all subfields examined 2-7 days after treatment in spite of increased phospho-CREB levels, perhaps as a consequence of corticosterone release by the serotonergic neurotoxin. The differential regulation of BDNF mRNA expression in the two brain regions examined appears to account for the enhanced TPH expression and the recovery of 5-HT levels in the frontal cortex, but not in the hippocampus, after neurotoxin treatment.