{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:49:27Z","timestamp":1787010567244,"version":"build-2736575974"},"posted":{"date-parts":[[2023,10,23]]},"group-title":"Neuroscience","reference-count":85,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,2,17]]},"abstract":"<jats:p>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, and that post-methamphetamine microglial repopulation attenuates drug-seeking following a 21-day period of abstinence. In contrast, microglial depletion during abstinence did 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.<\/jats:p>","DOI":"10.1101\/2023.10.19.563168","type":"posted-content","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:55:26Z","timestamp":1698108926000},"source":"Crossref","is-referenced-by-count":4,"title":["Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug"],"prefix":"10.64898","author":[{"given":"Samara J","family":"Vilca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V","family":"Margetts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Fleites","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claes","family":"Wahlestedt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis M","family":"Tuesta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023102801500565000_2023.10.19.563168v1.1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1316.009"},{"key":"2023102801500565000_2023.10.19.563168v1.2","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.pnpbp.2014.04.008","article-title":"Minocycline, an antibiotic with inhibitory effect on microglial activation, attenuates the maintenance and reinstatement of methamphetamine-seeking behavior in rat","volume":"53","year":"2014","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"2023102801500565000_2023.10.19.563168v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0192-3"},{"key":"2023102801500565000_2023.10.19.563168v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2777-8"},{"key":"2023102801500565000_2023.10.19.563168v1.5","doi-asserted-by":"crossref","first-page":"945548","DOI":"10.3389\/fpsyt.2022.945548","article-title":"Brain region- and sex-specific transcriptional profiles of microglia","volume":"13","year":"2022","journal-title":"Front Psychiatry"},{"issue":"5","key":"2023102801500565000_2023.10.19.563168v1.6","first-page":"301","article-title":"The need for speed: an update on methamphetamine addiction","volume":"31","year":"2006","journal-title":"J Psychiatry Neurosci"},{"key":"2023102801500565000_2023.10.19.563168v1.7","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03881-z"},{"issue":"2","key":"2023102801500565000_2023.10.19.563168v1.8","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1007\/s12035-014-8776-8","article-title":"Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat","volume":"51","year":"2015","journal-title":"Mol Neurobiol"},{"key":"2023102801500565000_2023.10.19.563168v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2011.06.013"},{"key":"2023102801500565000_2023.10.19.563168v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.01.038"},{"issue":"13","key":"2023102801500565000_2023.10.19.563168v1.11","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.1038\/s41386-021-01139-7","article-title":"Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine","volume":"46","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"2023102801500565000_2023.10.19.563168v1.12","unstructured":"CDC, N. 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