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

• Published in: Brain, behavior, and immunity Vol. 120; pp. 339 - 351
• Main Authors: Vilca, Samara J., Margetts, Alexander V., Höglund, Leon, Fleites, Isabella, Bystrom, Lauren L., Pollock, Tate A., Bourgain-Guglielmetti, Florence, Wahlestedt, Claes, Tuesta, Luis M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2024
• Subjects: Amphetamine-Related Disorders - metabolism; Animals; Bioinformatics; Brain - drug effects; Brain - metabolism; Central Nervous System Stimulants - pharmacology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Drug-Seeking; Drug-Seeking Behavior - drug effects; Drug-Seeking Behavior - physiology; Male; Methamphetamine; Methamphetamine - pharmacology; Mice; Mice, Inbred C57BL; Microglia; Microglia - drug effects; Microglia - metabolism; Neuroimmune; Neurotransmitter; Reinforcement, Psychology; RNA-seq; Self Administration; Striatum; Self-administration; Striatum; RNA-seq; Neuroimmune; Methamphetamine; Neurotransmitter; Drug-Seeking; Bioinformatics; Microglia
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2024.05.038

[Display omitted] •Methamphetamine induces gene expression changes in microglia that vary by phase of self-administration (maintenance; forced abstinence).•Methamphetamine induces morphological changes in microglia consistent with activation.•These transcriptional and morphological changes persist for up to 21 days after final exposure to methamphetamine.•Transcriptional analysis suggests possible involvement of microglia in regulation of neurotransmitter signaling.•PLX5622 treatment ablates microglia and increases methamphetamine-taking.•PLX5622 treatment during 21-day forced abstinence does not affect context-induced methamphetamine-seeking. 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 dorsal 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 associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.