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Differential Effects of Environment-Induced Changes in Body Temperature on Modafinil’s Actions Against Methamphetamine-Induced Striatal Toxicity in Mice

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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.

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Acknowledgments

Dr. Bisagno has been authorized to study drug abuse substances in animal models by A.N.M.A.T. (National Board of Medicine Food and Medical Technology, Ministerio de Salud, Argentina). Dr. Betina Gonzalez is a recipient of a Postdoctoral Award from Fundación Bunge y Born. This work is supported by Grants PIP 11420100100072, PICT 2012-0924, PICT 2012-1769, Argentina, and by NIH awards P20 GM103425 and P230 GM110702 to the Center for Translational Neuroscience.

Conflict of interest

Authors also report no conflict of interest, financial or otherwise, related directly or indirectly to this work.

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Authors and Affiliations

  1. 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

    Mariana Raineri, Betina González, Javier A. Muñiz, María Laura Gutiérrez, Carolina I. Ghanem & Veronica Bisagno

  2. Laboratorio de Fisiología y Biología Molecular, Instituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina

    Celeste Rivero-Echeto & Francisco J. Urbano

  3. Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, Baltimore, MD, USA

    Jean Lud Cadet

  4. Center for Translational Neuroscience, Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Edgar García-Rill

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  1. Mariana Raineri
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  2. Betina González
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  3. Celeste Rivero-Echeto
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  9. Francisco J. Urbano
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Correspondence to Veronica Bisagno.

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Raineri, M., González, B., Rivero-Echeto, C. et al. Differential Effects of Environment-Induced Changes in Body Temperature on Modafinil’s Actions Against Methamphetamine-Induced Striatal Toxicity in Mice. Neurotox Res 27, 71–83 (2015). https://doi.org/10.1007/s12640-014-9493-9

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