Abstract
Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4×5 mg/kg, i.p., 2 h apart) and modafinil co-administration (2×90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections) on glial cells (microglia and astroglia). We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum.
Highlights
Methamphetamine (METH) is an illicit drug of abuse that can cause neuropsychiatric and neurotoxic damage in humans and animals
Because the striatal pattern of dopamine damage caused by METH is more profound in lateral areas [12], we decided to assess the integrity of dopaminergic terminals by examining THimmunoreactive fibers in the dorsolateral region of the striatum
Neither modafinil by itself (MOD) nor the co-administration of modafinil and METH (M+M) altered TH levels compared to vehicle-treated mice (VEH) at any time point
Summary
Methamphetamine (METH) is an illicit drug of abuse that can cause neuropsychiatric and neurotoxic damage in humans and animals. METH mechanisms of action include the reversal of the dopamine transporter (DAT), resulting in dopamine (DA) efflux from dopaminergic terminals [1]. METH has pharmacological effects on a number of additional targets, including the vesicular monoamine transporter [2]. Neurotoxic effects of METH have been demonstrated in many species including rats, mice, guinea pigs, cats and monkeys (for a review, [2]). METH decreases striatal DAT binding as well as TH and DAT immunoreactivity [4,5,6]. Several studies have demonstrated that METH induces terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells [8,9]. METH-induced cell death occurs by activation of mitochondria- and endoplasmic reticulum dependent cell death pathways [10]
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