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TOXICOLOGY

Relationship between Temperature, Dopaminergic Neurotoxicity, and Plasma Drug Concentrations in Methamphetamine-Treated Squirrel Monkeys

Departments of Neurology (J.Y., G.H., P.S., G.R.) and Psychiatry and Behavioral Sciences (U.M.), The Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Experimental and Clinical Toxicology (M.M.), Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, Homburg (Saar), Germany

To examine the relationship between temperature (ambient and core), dopaminergic neurotoxicity, and plasma drug [methamphetamine (METH)] and metabolite [amphetamine (AMPH)] concentrations, two separate groups of squirrel monkeys (n = 4–5 per group) were treated with METH (1.25 mg/kg, given twice, 4 h apart) or vehicle (same schedule) at two different ambient temperatures (26 and 33°C). Core temperatures and plasma drug concentrations were measured during the period of drug exposure; striatal monoaminergic neuronal markers in the same monkeys were determined 1 week later. At the temperature range examined, the higher ambient temperature did not significantly enhance METH-induced hyperthermia or METH-induced dopaminergic neurotoxicity, although there were trends toward increases. Acute METH-induced increases in core temperature correlated highly and directly with subsequent decreases in striatal dopaminergic markers. Squirrel monkeys with the greatest increases in core temperature (and largest dopaminergic deficits) had the highest plasma drug metabolite (AMPH) concentrations. There was substantial interanimal variability, both with regard to elevations in core temperature and plasma drug concentrations. Pharmacokinetic studies in six additional squirrel monkeys revealed comparable individual differences in METH metabolism. These results, which provide the first available data on the within-subject relationship between temperature (ambient and core), plasma concentrations of METH (and AMPH), and subsequent dopaminergic neurotoxic changes, suggest that, as in rodents, core temperature can influence METH neurotoxicity in primates. In addition, they suggest that interanimal differences presently observed in thermal and neurotoxic responses to METH may be related to individual differences in drug metabolism.

Address correspondence to: Dr. George A. Ricaurte, Department of Neurology, Johns Hopkins Medical Institutions, 5501 Hopkins Bayview Circle, Rm. 5B.71E, Baltimore, MD 21224. E-mail: Ricaurte{at}jhmi.edu