Altered forebrain neurotransmitter responses to immobilization stress following 3,4-methylenedioxymethamphetamine.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is an increasingly popular drug of abuse that acts as a neurotoxin to forebrain serotonin neurons. The neurochemical effects of the serotonin depletion following high doses of MDMA were investigated in response to acute immobilization stress. Male rats were treated with a neurotoxic dosing regimen of MDMA (10 mg/kg, i.p. every 2 h for four injections) or equivalent doses of saline. Seven days after treatment, in vivo microdialysis was used to assess extracellular dopamine and serotonin in the dorsal hippocampus and prefrontal cortex during 1 h of immobilization stress. In saline treated control rats, serotonin in the hippocampus and serotonin and dopamine in the prefrontal cortex were increased during immobilization stress. Rats pretreated with MDMA, however, showed blunted neurotransmitter responses in the hippocampus and the prefrontal cortex. In the drug pretreated rats, basal serotonin levels in the hippocampus, but not the prefrontal cortex, were lower compared to saline pretreated controls. Stress-induced increases in plasma corticosterone and body temperature were not affected by the pretreatment condition. From these studies we suggest that depletion of serotonin stores in terminal regions with the neurotoxin MDMA compromises the ability of the serotonergic neurons to activate central systems that respond to stressful stimuli. This altered responsiveness may have implications for long-term functional consequences of MDMA abuse as well as the interactions between the serotonergic system and stress.