The effects of previous exposure to chronic methamphetamine on drug-seeking behavior and neurodegeneration in male and female mice

Purpose: Recreational and medical use of stimulants among young adults have gained popularity in the United States over the last decade, with amphetamine compounds becoming the second most common illicit drug used in college students. Although amphetamine stimulants have proven to be safe and efficacious in children and adults with Attention Deficit and Hyperactivity Disorder (ADHD) when used as prescribed, these drugs can have significant adverse side effects such as an increased potential of recreational abuse liability, dependence, and neurotoxicity. There are known sex differences in drug abuse, in which women have lower rates of illicit drug use, but use more of the drug, reach dependence faster and have more adverse effects. We hypothesize that females may be more vulnerable to the reinforcing effects of METH as well as METH-induced neurotoxicity and dopaminergic dysregulation. Our study investigated the effects of early chronic exposure to the prototypical stimulant, methamphetamine (METH), at a dose designed to emulate human therapeutic dosing, on abuse potential and biochemical markers of dopaminergic function and neurodegeneration in male and female mice. Methods: Groups of 4-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 4 weeks. METH (0.5 mg/kg)-induced conditioned place preference (CPP) was tested in mice to determine the reinforcing effects of previous METH exposure. Mice were randomly assigned to either: Experiment I (short-term) in which male and female mice underwent CPP 13 days after injection cessation or Experiment II (long-term) in which female mice underwent CPP 5 months after injection cessation. Following behavioral testing, the animals were euthanized and striatum and midbrain were collected for biochemical testing of dopaminergic function and neurodegeneration. Results: In Experiment I, chronic METH exposure induced drug preference for subsequent doses of METH especially in males, and downregulated dopaminergic markers in males and induced apoptosis in females. In Experiment II, when CPP was performed 5 months after injection cessation, females with prior exposure to METH did not exhibit drug preference to subsequent doses of METH and there were no effects on markers of neurodegeneration or dopaminergic function. Conclusion: Previous exposure to METH induced a heightened sensitivity to subsequent doses of METH especially in males. While the effect in females was smaller, it disappeared in the long-term suggesting that this heightened sensitivity does not last over time. The increase in sensitivity was supported by alterations in the dopaminergic system in males. These outcomes suggest sex differences in response to prior METH exposure, and that these effects may not be long-lasting.