ROLE OF HYPOTHERMIA IN THE MECHANISM OF PROTECTION AGAINST SEROTONERGIC TOXICITY .1. EXPERIMENTS USING 3,4-METHYLENEDIOXYMETHAMPHETAMINE, DIZOCILPINE, CGS-19755 AND NBQX

High doses of 3,4-methylenedioxymethamphetamine (MDMA) have been shown to cause long-lasting depletions of central serotonin (5-HT) which ar e indicative of neuronal toxicity. The noncompetitive N-methyl-D-aspar tate (NMDA) receptor antagonist dizocilpine (DZ) attenuates depletions of 5-HT induced by MDMA. Because DZ has been shown to induce hypother mia in rat models of ischemia, the purpose of this study was to assess whether DZ and two other glutamate antagonists, CGS 19755 (CGS) and - dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), protect agai nst MDMA-induced 5-HT depletions by induction of hypothermia. Male Spr ague-Dawley rats were injected with either saline (SAL), DZ (2.5 mg/kg ), CGS (25.0 or 50.0 mg/kg x 2 injections) or NBQX (30.0 mg/kg x 2 inj ections or 55.0 mg/kg x 3 injections) followed by either MDMA (40.0 mg /kg) or SAL. Core body temperature (TEMP) was monitored for 4 h or lon ger using radiotelemetry. Base-line TEMP was between 37.0 and 37.6 deg rees C. Administration of DZ with MDMA decreased TEMP to 34.0 +/- 0.39 degrees C within 2 h of the MDMA injection, and also protected agains t serotonergic toxicity. Neither SAL/MDMA nor DZ/SAL had an effect on TEMP over the same period. When rats were treated with DZ/MDMA and TEM P was maintained between 38.4 degrees C and 40.4 degrees C for 4 h, pr otection against 5-HT depletion was abolished. Coadministration of the competitive NMDA antagonist CGS with MDMA resulted in a decrease in T EMP to 34.5 +/- 0.27 degrees C, and provided partial protection agains t 5-HT depletions. When the AMPA receptor antagonist NBQX was administ ered with MDMA, TEMP did not differ from rats treated with SAL/MDMA, n or did NBQX protect against 5-HT depletions. The data from this study show that coadministration of NMDA antagonists with MDMA induces hypot hermia in dose combinations which protect against serotonergic toxicit y, and neuroprotection by DZ is abolished when TEMP is maintained abov e 38.4 degrees C. These data indicate that hypothermia induced by NMDA receptor antagonism plays a role in protection against serotonergic t oxicity.