COADMINISTRATION OF MDMA WITH DRUGS THAT PROTECT AGAINST MDMA NEUROTOXICITY PRODUCES DIFFERENT EFFECTS ON BODY-TEMPERATURE IN THE RAT

The substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) h as been shown to be neurotoxic to serotonin (5HT) terminals in the rat , and rat body temperature (TEMP) has been shown to affect this neurot oxicity. This study looked ai:the effect on CORE TEMP of three drugs t hat protect against MDMA neurotoxicity in the rat, Male Holtzmann rats were injected with a control saline (SAL) injection or with ketanseri n (KET; 6 mg/kg), alpha-methyl-p-tyrosine (AMPT; 75 mg/kg) or fluoxeti ne (FLUOX; 10 mg/kg) before a 40-mg/kg MDMA or SAL injection. CORE TEM P was recorded throughout the study using a noninvasive peritoneally i mplanted temperature probe. Rats pretreated with KET had net change in CORE TEMP until MDMA was injected, at which time an immediate hypothe rmia was seen that continued for 180 minutes, with a peak low of 34.7 degrees C. Rats treated with AMPT had no change in CORE TEMP until the MDMA was injected, at which time an immediate hypothermia was seen th at continued for 240 min., with a peak low of 34.3 degrees C. Two week s later, brain regions were analyzed for 5-HT and 5-hydroxindole aceti c acid levels. MDMA produced significant (P < .05) decreases in 5-HT a nd 5-hydroxindole acetic acid levels in the frontal cortex, somatosens ory cortex, striatum and hippocampus, and pretreatment with KET or AMP T prevented these depletions. When rats were given the KET/MDMA or AMP T/MDMA drug injections and warmed to prevent hypothermia, the protecti on against neurotoxicity was removed, which indicated that the hypothe rmia mediated the protective effects of KET and AMPT. In comparison wi th the hypothermia seen with AMPT or KET pretreatment, pretreatment wi th FLUOX had no effect on CORE TEMP. The rats given the FLUOX/MDMA tre atment did not have different CORE TEMPs than rats given SAL/MDMA. The FLUOX pretreatment protected against MDMA-induced 5-HT and 5-hydroxin dole acetic acid depletions in the frontal cortex, somatosensory corte x, striatum and hippocampus. This study suggests that a decrease in CO RE TEMP may be a mechanism of protection against MDMA neurotoxicity by some drugs but that there is also a mechanism of protection that is i ndependent of a change in body temperature.