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Ibudilast, a toll\u2010like receptor 4 (TLR4) inhibitor, has been shown to reduce METH\u2010induced neuroinflammation and self\u2010administration, but its specific role in neuronal TLR4 signalling and associated behavioural outcomes remains poorly understood. This study examined Ibudilast's effects on METH reward, drug\u2010seeking behaviour, and TLR4 signalling in a rat self\u2010administration model. Ibudilast was found to dose\u2010dependently reduce METH intake and motivation for the drug, as evidenced by a downward shift in the dose\u2013response curve and a decrease in breakpoint. Additionally, Ibudilast suppressed both cue\u2010 and METH priming\u2010induced drug\u2010seeking behaviours. Western blot analysis revealed elevated TLR4, p\u2010NF\u2010\u03baB and IL\u20106 in the prefrontal cortex after 14\u2009days of METH self\u2010administration. These increases were significantly attenuated by Ibudilast treatment. Furthermore, local administration of Ibudilast in the prefrontal cortex led to a reduction in METH intake and motivation, as well as decreased TLR4 expression in this brain region. Immunofluorescence staining was revealed that TLR4 was expressed predominantly in neurons and microglia, with METH\u2010induced upregulation of neuronal TLR4 being linked to apoptosis. Ibudilast restored normal spatial interactions between neurons and microglia, thereby mitigating neuroinflammation and neuronal damage. Furthermore, local injection of Ibudilast in the prefrontal cortex led to a reduction in METH intake and motivation, as well as decreased expression of TLR4 in the brain region. These findings underscore the critical role of neuronal TLR4 in METH addiction and highlight Ibudilast's therapeutic potential in addressing METH\u2010related neuroinflammation and behavioural dysregulation.<\/jats:p>","DOI":"10.1111\/adb.70033","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T11:55:42Z","timestamp":1745582142000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Ibudilast\u2010Mediated Suppression of Neuronal TLR4 in the Prefrontal Cortex Mitigates Methamphetamine\u2010Induced Neuroinflammation and Addictive Behaviours"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1794-6335","authenticated-orcid":false,"given":"Fangmin","family":"Wang","sequence":"first","affiliation":[{"name":"Zhejiang Provincial Key Lab of Addiction Research The Affiliated Kangning Hospital of Ningbo University  Ningbo People's Republic of China"},{"name":"Department of Psychiatry The Affiliated Kangning Hospital of Ningbo University  People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huizhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Lab of Addiction Research The Affiliated Kangning Hospital of Ningbo University  Ningbo People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics The Affiliated Lihuili Hospital of Ningbo University  Ningbo P. 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