JPET 316:1210-1218, 2006

Relationship between Temperature, Dopaminergic Neurotoxicity, and Plasma Drug Concentrations in Methamphetamine-Treated Squirrel Monkeys
 
Jie Yuan, George Hatzidimitriou, Pranav Suthar, Melanie Mueller, Una McCann, and George Ricaurte

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

Received October 4, 2005; accepted November 14, 2005.

Drug Administration.
d-Methamphetamine (or vehicle) was administered orally. Oral administration was accomplished by orogastric gavage, with the animal gently restrained in a Plexiglas chair during the procedure. Dose selection was based upon pilot studies and published reports indicating that two doses of METH given hours apart have the potential to produce lasting effects on brain DA neurons in nonhuman primates (Melega et al., 1998 ). We ultimately selected a dose of 1.25 mg/kg, given twice at a 4-h interval, because pilot studies showed that this dosage regimen is well tolerated and produced a modest reduction in striatal DA neuronal markers 1 week later, thus leaving room for a possible enhancement by a higher ambient temperature (33°C instead of 26°C). Drug (or vehicle) administration was performed at 11:00 AM and 3:00 PM, so that assessment of effects on core temperature took place during a relatively stable period of the circadian temperature cycle (see Results).

Overall Design.
Two different groups (n = 4–5 per group) of drug-naive animals were used to test the effects of increased ambient temperature on METH-induced changes in core temperature and subsequent DA neurotoxicity (i.e., five monkeys received vehicle and METH at 26°C and four different monkeys received vehicle and METH at 33°C) (Table 1). The rationale for the temperatures selected (26 and 33°C) was as follows. An ambient temperature of 26°C was selected because it is considered to be in the thermoneutral range for the squirrel monkey (Stitt and Hardy, 1971 ; Robinson and Fuller, 1999 ); an ambient temperature of 33°C was used as a "warm" environment because it is toward the high end of the thermoneutral range for the squirrel monkey (Stitt and Hardy, 1971 ; Robinson et al., 1993 ) and because studies in rodents indicate that a 7°C increase in ambient temperature increases METH neurotoxicity (Callahan et al., 1998 ).