Modafinil maintains protective effects on methamphetamine-induced toxicity at different ambient temperatures

V. Bisagno¹, M. Raineri¹, B. Gonzalez¹, N. Colettis², E. Garcia-Rill³, J.L. Cadet⁴, F.J. Urbano². ¹Instituto de Investigaciones Farmacológicas, ININFA (UBA-CONICET), Argentina; ²Instituto de Fisiología, Biología Molecular y Neurociencias, IFIByNE (UBA-CONICET), Argentina; ³Center for Translational Neuroscience, University of Arkansas for Medical Sciences, United States; ⁴Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, United States

Background: Methamphetamine (METH) is an illicit drug of abuse that can cause neuropsychiatric and neurotoxic damage in humans and animals. We have previously shown that modafinil can interfere with METH actions and counteract METH-induced hyperthermia, dopamine toxicity, and neuroinflammation in the striatum.

Methods: To clarify whether temperature regulation might have a role in modafinil neuroprotection against METH, we evaluated the effect of a toxic METH binge in female C57BL/6 mice (4×5 mg/kg, intraperitoneal [i.p.]) and modafinil co-administration (2×90 mg/kg, i.p.) at two ambient temperatures: 14±1°C and 29±1°C. Body temperatures were recorded throughout the binge administration. Dopaminergic and inflammatory markers were measured in striatal tissue 6 days after treatments.

Results: At 29°C, METH, given alone, induced hyperthermia (p<0.05) in rats; rats treated with the combination of METH and modafinil (Me+Mo) also showed hyperthermia (p<0.05) at that temperature. Modafinil partially prevented the decreases in tyrosine hydroxylase (TH) expression and the increases in glial fibrillary acidic protein immunoreactivity (p<0.05); the drug also prevented METH-induced dopamine transporter (DAT) decrease in the striatum (p<0.05). Interestingly, we found significant correlations between METH-induced maximum body temperature and TH (R=–0.94; p=2.8×10^-7) and DAT (R=–0.70; p=3.9×10^-3) levels only for the METH alone group. At 14°C, none of the groups showed hyperthermia or decreases in TH and DAT expression. METH-induced astrocytosis was completely prevented by modafinil. The Me+Mo group showed hypothermia (p<0.05) in comparison with other groups.

Conclusions: These findings support our previous reports that modafinil exerts protective effects against METH toxicity. Our observations suggest that modafinil-induced protection is mediated, in part, by attenuating METH-induced hyperthermia.