Role of hypothermia in the mechanism of protection against serotonergic toxicity. I. Experiments using 3,4-methylenedioxymethamphetamine, dizocilpine, CGS 19755 and NBQX.
Journal of Pharmacology and Experimental Therapeutics February 1, 1995 DOI: 10.1016/s0022-3565(25)24411-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled animal experiment Peer reviewed |
|---|---|
| Population | Male Sprague-Dawley rats |
| Interventions | Dizocilpine (DZ) CGS 19755 (CGS) NBQX MDMA saline |
| Dose | DZ 2.5 mg/kg; CGS 25.0 or 50.0 mg/kg x 2 injections; NBQX 30.0 mg/kg x 2 injections or 55.0 mg/kg x 3 injections; MDMA 40.0 mg/kg |
| Duration | Core body temperature monitored for 4 h or longer |
| Measures | Core body temperature (radiotelemetry), serotonin (5-HT) depletion |
| Topics | MDMA Serotonin |
| Key findings | Dizocilpine protected against MDMA-induced serotonin depletion in rats while lowering body temperature to about 34.0 degrees C, and this protection was abolished when body temperature was maintained at 38.4-40.4 degrees C. The authors conclude the protection may be mediated by hypothermia. The related antagonist CGS also lowered temperature and gave partial protection. |
Abstract
High doses of 3,4-methylenedioxymethamphetamine (MDMA) have been shown to cause long-lasting depletions of central serotonin (5-HT) which are indicative of neuronal toxicity. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (DZ) attenuates depletions of 5-HT induced by MDMA. Because DZ has been shown to induce hypothermia in rat models of ischemia, the purpose of this study was to assess whether DZ and two other glutamate antagonists, CGS 19755 (CGS) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), protect against MDMA-induced 5-HT depletions by induction of hypothermia. Male Sprague-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 injections 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 longer using radiotelemetry. Base-line TEMP was between 37.0 and 37.6 degrees 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 against 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 TEMP was maintained between 38.4 degrees C and 40.4 degrees C for 4 h, protection against 5-HT depletion was abolished. Coadministration of the competitive NMDA antagonist CGS with MDMA-resulted in a decrease in TEMP to 34.5 +/- 0.27 degrees C, and provided partial protection against 5-HT depletions.(ABSTRACT TRUNCATED AT 250 WORDS)