Attenuated methamphetamine induced neurotoxicity by modafinil administration in mice

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 psy- chostimulant addiction. In this study we tested possible neuroprotective effects of modafinil after toxic METH administration in mice. We evaluated the effect of modafi- nil (two injections of either 90 or 180 mg/kg) and METH binge (3 3 7 mg/kg i.p. injec- tions, 3-h apart) coadministration on DA striatal content, TH immunoreactivity in striatal areas and spontaneous locomotor activity. We also investigated acute locomo- tor 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 dis- tance traveled in an open field compared with METH groups. We observed an incre- ment 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. Synapse 65:1087-1098, 2011. V C 2011 Wiley-Liss, Inc.