Role of hypothermia in the mechanism of protection against serotonergic toxicity. II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan.
Several amphetamine analogs, when administered in high-dose regimens, have been shown to cause long-lasting depletions of central serotonin (5-HT), which are indicative of neuronal toxicity. These depletions and the resulting toxicity can be attenuated pharmacologically or by lowering ambient temperature. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (DZ) blocks depletion of 5-HT induced by methamphetamine (METH) and p-chloroamphetamine (PCA), but not fenfluramine (FEN). This study investigated whether the effects of DZ and another calcium channel antagonist, dextromethorphan (DEX), are due to induction of hypothermia. Male Sprague-Dawley rats were injected with either saline (SAL), DZ (1 or 2 injections of 2.5 mg/kg), or DEX (75.0 mg/kg) followed by either SAL, METH (4 injections of 10.0 mg/kg), PCA (1 injection of 10.0 mg/kg) or FEN (2 or 4 injections of 12.5 mg/kg). Core body temperature (TEMP) was monitored for 4 h or longer with radiotelemetry. Base-line TEMP was between 37.0 and 37.6 degrees C. SAL/METH caused a significant increase in TEMP which peaked at 40.8 +/- 0.50 degrees C after the last injection. Coadministration of DZ with METH caused TEMP to decrease to 33.8 +/- 0.30 degrees C within 2 h of the first injection and lasting more than 3 h, and protected against depletion of 5-HT. SAL/PCA caused a small increase in TEMP to 37.7 +/- 0.36 degrees C, whereas coadministration of DZ with PCA decreased TEMP to 35.2 +/- 0.50 degrees C, lasting 2 h, in a dose regimen which has been shown to be neuroprotective.(ABSTRACT TRUNCATED AT 250 WORDS)
University of Chicago, Department of Pharmacological and Physiological Sciences, Illinois.
G M
GM
Farfel
L S
LS
Seiden
D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D003915:Dextromethorphan / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D005277:Fenfluramine / Q000633:toxicity*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis*; D010133:p-Chloroamphetamine / Q000633:toxicity*
D005277:Fenfluramine; D012701:Serotonin; D008694:Methamphetamine; D010133:p-Chloroamphetamine; D016291:Dizocilpine Maleate; D003915:Dextromethorphan