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 , 2h apart; modafinil (90mg/kg) was injected twice, 1h 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 six days after treatments and processed for TH, DAT, GFAP and c-Fos immunohistochemistry. Exposure to hot ambient temperature exacerbated METH toxicity evidenced by sriatal 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.

The Role of HSP90α in Methamphetamine/Hyperthermia-Induced Necroptosis in Rat Striatal Neurons

“…In the present study, a binge dose of METH significantly increased the core body temperature to 38.5-39.5°C compared with the saline controls. The measured core body temperature was slightly lower than that observed in Chauhan et al's study, which may be caused by the differences in the experimental environment (Raineri et al, 2015), the weight of the rats (Bowyer et al, 1993), and the experimental equipment. Thus, we performed our HT experiments in vitro at 39.5°C.…”

Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice

“…with a 3-hour interval between injections as described in detail previously and shown to cause significant striatal toxicity ( Granado et al, 2010, 2011a ; Ares-Santos et al, 2012, 2014 ; ElAli et al, 2012 ; Urrutia et al, 2013, 2014 ). This regimen is very close to other studies where 4 doses of 5mg/kg at 2-hour intervals were used to induce toxicity ( Good et al, 2011 ; Chiu et al, 2014 ; Raineri et al, 2015 ). Control mice were given saline.…”

Wake-Promoting and EEG Spectral Effects of Modafinil After Acute or Chronic Administration in the R6/2 Mouse Model of Huntington's Disease

“…This is particularly relevant, as the accumulation of pro-inflammatory cytokines has been demonstrated to induce neuroinflammation in HD [ 64 ]. Moreover, modafinil has been shown to promote hippocampal neurogenesis [ 65 ] and synaptic plasticity [ 66 , 67 ], and its possible neuroprotective role has also been reported against methamphetamine induced striatal toxicity [ 68 ]. Thus, there are multiple mechanisms whereby modafinil might be beneficial in HD.…”