Early Chronic Methamphetamine Exposure Induces Cognitive Impairments and Oxidative Damage in Adult Mice

Abstract

Prescription stimulant misuse among young adults has gained popularity in the United States over the last decade, with amphetamine compounds becoming the second most common illicit drug used in college students. Misuse of these drugs can pose serious risks due to their high potential for abuse that can lead to dependency and neurotoxicity. Furthermore, there are prominent sex differences in psychostimulant use: men use more frequently and women have higher success rates in treatment but are more vulnerable to dependence and adverse effects. Psychostimulants, even at moderate doses, have been shown to promote oxidative stress, via auto-oxidation or metabolism of accumulated redox active dopamine. Oxidative stress has also been implicated in neurobehavioral impairments. Therefore, exposure to psychostimulants as a consequence of abuse would provide a second hit predicted to increase brain impairments. Moreover, the mesocorticolimbic pathway, a critical dopaminergic pathway, is particularly vulnerable to oxidative insults, and reveals sex-dependent differences in dopamine dynamics. We hypothesized that oxidative stress may act as a prominent cellular mechanism in mediating psychostimulant-induced neurotoxicity and neurobehavioral deficits. The purpose of this pilot study was to determine the short-term consequences of chronic, low toxic dosing of the prototypical psychostimulant, methamphetamine (METH), on cognition and markers of oxidative stress and dopaminergic function. Groups of young male and female (4-month-old) C57BL/6J mice received non-contingent intraperitoneal injections of either saline or methamphetamine (1.4 mg/kg) twice a day for 4 weeks. Two weeks following the last injection, animals were tested for cognitive function using 3 different tests: Morris water maze, active avoidance, and fear conditioning. After the completion of behavioral testing, brain regions were dissected and markers of oxidative stress and dopaminergic function were assayed. METH administration appeared to induce deficits in spatial learning and memory in both males and females, and in active avoidance and fear conditioning response in female mice only. Markers of dopaminergic function do not seem to be majorly affected by METH administration, while markers of lipid peroxidation were increased in the cortex and hippocampus of METH-treated females. These preliminary results suggest that chronic administration of METH induced impairments in cognitive function and changes in oxidative stress. These data indicate functional and biochemical changes that may have long-term consequences on brain function which will be the focus of future studies.