Attenuated methamphetamine induced neurotoxicity by modafinil administration in mice

Abstract

Methamphetamine (METH) is a highly addictive drug that might induce neurotoxicity. Clinical trials have reported that modafinil, a wake-promoting agent used to treat sleep disorders, may have some efficacy for the treatment of psychostimulant addiction. In this study we tested possible neuroprotective effects of modafinil after toxic METH administration in mice. We evaluated the effect of modafinil (two injections of either 90 or 180 mg/kg) and METH binge (3 × 7 mg/kg i.p. injections, 3-h apart) coadministration on DA striatal content, TH immunoreactivity in striatal areas and spontaneous locomotor activity. We also investigated acute locomotor activity and stereotypy profile in mice treated with a single METH dose (2 and 7 mg/kg) pretreated with modafinil (90 and 180 mg/kg). We found that mice treated with a METH binge showed a marked decrease in DA and dopaminergic metabolites as well as lower levels of TH immunoreactivity in the dorsal striatum. Pretreatment with modafinil (both 90 and 180 mg/kg) attenuated these effects but did not prevent METH induced decrease in locomotion. We also found that groups that received the combination of both modafinil and single dose METH showed a decrease in total distance traveled in an open field compared with METH groups. We observed an increment in the time mice expended doing stereotypic movements (continuous sniffing) in the group that received the combination of both METH and modafinil (i.e., decreasing locomotion). Our results suggest a possible protective role of modafinil against METH acute striatal toxicity.

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

“…Nevertheless, modafinil maintained its neuroprotective properties against METH-induced alterations in the striatum at different ambient temperatures. Results from the present study suggest that even under rather demanding environmental conditions (high or cold ambient temperatures) modafinil was still able to interfere with METH harmful effects as it was previously shown for METH-induced changes in biochemical markers (Raineri et al, 2011; 2012; Zolkowska et al, 2009) and behavioral functions (Zolkowska et al, 2009; Gonzalez et al, 2014, Reichel et al, 2014). Moreover, we found that modafinil (by itself) did not alter the level of any dopaminergic marker in the striatum even at high ambient temperatures.…”

“…Moreover, modafinil enhances electrotonic coupling by increasing the effectiveness of gap junction communication between neurons (Urbano et al, 2007; Garcia-Rill et al, 2007). Interestingly, modafinil can also protect against METH-induced DA depletion and reductions in TH and DAT levels in the striatum (Raineri et al, 2011). Furthermore, modafinil also attenuated METH-induced hyperthermia and glial activation in striatal tissue (Raineri et al, 2012).…”

“…Furthermore, modafinil also attenuated METH-induced hyperthermia and glial activation in striatal tissue (Raineri et al, 2012). This protective effect of modafinil may be secondary to its effects as a DAT blocker (Zolkowska et al, 2009; Raineri et al, 2011; 2012). Nevertheless, the protective properties of modafinil could also be attributed to a direct effect on thermoregulatory responses to METH treatment (i.e.…”

Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice

“…In addition, modafinil enhances electrotonic coupling by increasing the effectiveness of gap junctions between neurons (Urbano et al, 2007; Garcia-Rill et al, 2007). We also demonstrated that modafinil can protect against METH toxicity (Raineri et al, 2011; 2012). Specifically, modafinil was able to prevent METH-induced toxic effects that included DA depletion and reductions in tyrosine hydroxylase (TH) and DAT levels in the striatum (Raineri et al, 2011).…”

“…We also demonstrated that modafinil can protect against METH toxicity (Raineri et al, 2011; 2012). Specifically, modafinil was able to prevent METH-induced toxic effects that included DA depletion and reductions in tyrosine hydroxylase (TH) and DAT levels in the striatum (Raineri et al, 2011). Furthermore, modafinil also attenuated METH-induced hyperthermia, glial activation, and increased expression of proapoptotic proteins (Raineri et al, 2012).…”