Effects of chronic methamphetamine exposure on rewarding behavior and neurodegeneration markers in adult mice

Recreational and medical use of stimulants among young adults have gained popularity in the United States over the last decade and their use may increase vulnerability to brain biochemical changes and addictive behaviors. The long-term effects of chronic stimulant exposure in later adulthood have not been fully elucidated. Our study investigated whether chronic exposure to methamphetamine (METH), at a dose designed to emulate human therapeutic dosing for ADHD, would promote biochemical alterations and affect sensitivity to the rewarding effects of subsequent METH dosing. Groups of 3.5-month-old male and female C57BL/6J mice were administered non-contingent intraperitoneal injections of either saline or METH (1.4 mg/kg) twice a day for 1 month (5 days/week). METH (0.5 mg/kg)-induced conditioned place preference (CPP) was tested in mice to determine the effects of previous METH exposure on reward-related behavior. Mice were randomly assigned to Experiment I (males and females) or Experiment II (females only) in which CPP testing was respectively performed either 0.5 or 5 months after the end of METH injections, at ~5 or 10 months old respectively. The midbrain and striatum, regions involved in reward circuit, were assessed for markers associated with neurotoxicity, dopaminergic function, neuroinflammation and epigenetic changes after behavioral testing. Previous exposure to chronic METH did not have significant short-term effects on CPP response but led to a decreased CPP response in 10-month-old females. Previous exposure to METH induced some short-term changes to biochemical markers measured in a brain region and sex-dependent manner, while long-term changes were only observed with GFAP and KDM5C. In conclusion, our data suggest sex- and post-exposure duration-dependent outcomes and warrant further exploration of the long-term neurobehavioral consequences of psychostimulant use in both sexes.