The effects of developmental age on (+/-)-3,4-methylenedioxymethamphetamine (MDMA)-induced reductions in 5-hydroxytryptamine (5-HT) content and 5-HT reuptake sites were investigated in conjunction with the effects of developmental age on MDMA-induced thermoregulatory responses. MDMA was administered to rats at postnatal days (PND) 10, 40 and 70 in a range of ambient temperature environments (10 degrees C, 25 degrees C and 33 degrees C). Animals were monitored for alterations in body temperature and sacrificed 1 week after MDMA administration. MDMA administration at PND 10 did not result in persistent reductions in 5-HT content or 5-HT reuptake sites in frontal cortex, nor could a hyperthermic response be elicited. In contrast, MDMA administration at PND 40 and PND 70 resulted in a hypothermic response in cold environments (10 degrees C) and a hyperthermic response in warm environments (> or = 25 degrees C). When hypothermia was observed after MDMA (10 degrees C environment), long-term reductions in 5-HT content and 5-HT reuptake sites were significantly attenuated or abolished. Conversely, when a hyperthermic response was observed (25 degrees C and 33 degrees C environments), long-term MDMA-induced reductions in 5-HT content and 5-HT reuptake sites were significantly enhanced. Thus, thermal responses significantly correlated with MDMA-induced reductions in 5-HT content and 5-HT reuptake sites. These experiments demonstrate a role for hyperthermia in the expression of serotonergic neurotoxicity after MDMA administration.