Age-dependent sensitivity of rats to the long-term effects of the serotonergic neurotoxicant (+/-)-3,4-methylenedioxymethamphetamine (MDMA) correlates with the magnitude of the MDMA-induced thermal response.

In rats, the age at which MDMA is given determines both the body-temperature response and the long-term damage to serotonin neurons. In 10-day-old pups, MDMA produced no lasting loss of serotonin or its reuptake sites and no hyperthermia. In 40- and 70-day-old rats, MDMA caused hypothermia in a cold environment (10°C) and hyperthermia in warm environments (25°C or 33°C). When hypothermia occurred, the long-term reductions in serotonin content and reuptake sites were significantly weakened or absent. When hyperthermia occurred, those reductions were significantly worsened. Body temperature changes strongly correlated with the degree of serotonin damage, indicating that hyperthermia plays a key role in MDMA's serotonergic neurotoxicity.

Study at a glance

Abstract

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.