title: Differential effects of environment-induced changes in body temperature on modafinil's actions against methamphetamine-induced striatal toxicity in mice.
abstract: Methamphetamine (METH) exposure can produce hyperthermia that might lead to toxicity and death. Modafinil is a wake-promoting compound that is also been prescribed off-label to treat METH dependence. Modafinil has shown neuroprotective properties against METH harmful effects in animal models. The goal of the present study was to test if the prevention of hyperthermia might play a role on the neuroprotective actions of modafinil against METH toxicity using various ambient temperatures. METH was administered to female C57BL/6 mice in a binge regimen: 4 × 5 mg/kg, 2 h apart; modafinil (90 mg/kg) was injected twice, 1 h before first and fourth METH injections. Drugs were given at cold ambient temperature (14 °C) or hot ambient temperature (29 °C). Body temperature was measured during treatments. Brains were dissected out 6 days after treatments and processed for tyrosine hydroxylase (TH), dopamine transporter (DAT), GFAP and c-Fos immunohistochemistry. Exposure to hot ambient temperature exacerbated METH toxicity evidenced by striatal reductions in TH and DAT and increased GFAP immmunoreactivity. Modafinil counteracted reductions in TH and DAT, but failed to block astroglial activation. At both ambient temperatures tested modafinil did induce increments in GFAP, but the magnitude was significantly lower than the one induced by METH. Both drugs induced increases in c-Fos positive nuclei; modafinil did not block this effect. Our results suggest that protective effects of modafinil against METH-induced neurotoxicity may be dependent, in part, to its hypothermic effects. Nevertheless, modafinil maintained some protective properties on METH-induced alterations in the striatum at different ambient temperatures.
authors.affiliation: Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (ININFA-UBA-CONICET), Ciudad Autónoma de Buenos Aires, Junín 956, piso 5, C1113, Buenos Aires, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Raineri
authors.forename: Betina
authors.initials: B
authors.lastname: González
authors.forename: Celeste
authors.initials: C
authors.lastname: Rivero-Echeto
authors.forename: Javier A
authors.initials: JA
authors.lastname: Muñiz
authors.forename: María Laura
authors.initials: ML
authors.lastname: Gutiérrez
authors.forename: Carolina I
authors.initials: CI
authors.lastname: Ghanem
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
authors.forename: Edgar
authors.initials: E
authors.lastname: García-Rill
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Urbano
authors.forename: Veronica
authors.initials: V
authors.lastname: Bisagno
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D003080:Cold Temperature; D015259:Dopamine Agents / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D006358:Hot Temperature; D007035:Hypothermia / Q000139:chemically induced* / Q000517:prevention & control*; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D000077408:Modafinil; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D018696:Neuroprotective Agents; D016760:Proto-Oncogene Proteins c-fos; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D000077408:Modafinil