Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes related to protein folding, mRNA processing, immune signaling, and neurotransmission in striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analysis. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion did not alter methamphetamine-seeking behavior following 21 days of abstinence, highlighting the complexity of drug-seeking behaviors. Taken together, these results suggest that methamphetamine induces both short and long-term changes in striatal microglia that contribute to altered drug-taking behavior and may be leveraged for preclinical development of methamphetamine cessation therapeutics.