BEHAVIORAL AND MICROBIAL CONSEQUENCES OF METHAMPHETAMINE EXPOSURE AND WITHDRAWAL IN RATS

Rationale: Methamphetamine use disorder (MuD) continues to be a global health problem that results in behavioral changes associated with addiction and neurocognitive decline. Despite the profound burden of this disorder, currently, there are no FDA-approved medications for the treatment of MuD. Accumulative evidence reveals the influence of gut microbiota on the brain, behavior, and health as a part of the gut-brain axis but its involvement in modulating this substance use disorder remains poorly understood. Objective: We sought to determine whether methamphetamine exposure and withdrawal alter the intestinal gut microbiota and characterize withdrawal-induced behavioral changes in male and female rodents. We also sought to explore whether the administration of probiotics alters gut microbial composition and blocks the development of anxiety- and depressive-like behavior in METH-exposed male and female rats. Methods: Male and female Sprague-Dawley rats were administered methamphetamine injections (2 mg/kg; s.c.) or saline injection twice daily with either a combination of probiotics or placebo solution (4 groups/n=8 per group) for 14 consecutive days. On various days before, during, and after administration, fecal samples were collected, and tests of anxiety- and depressive-like behaviors were conducted. Results: Methamphetamine exposure and its withdrawal altered gut microbial composition; and induced anxiety-like behavior in females and anxiety- and depressive-like behavior in males. Two weeks of supplementation with Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 blocked the development of methamphetamine-induced anxiety- and depressive-like behavior in males and restored gut microbial composition more in females. Conclusions: These findings provide direct evidence that methamphetamine and its withdrawal cause gut dysbiosis in both sexes and that the latter is associated with anxiety- and depressive-like behavior in males. The alternative therapies such as probiotics hold potential in treating METH-induced behavioral changes and restoring gut microbial composition in a sex-specific manner. Our observations will contribute to a better understanding of the function of gut microbiota in the process of substance use disorders and guide the choice of target therapeutics.