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Evidence from both animal studies and human genetic association studies has demonstrated that dysregulation of GPR139 expression and function is linked to aberrant behaviors, cognitive deficits, alterations in sleep and alertness, and substance abuse and withdrawal. Animal knockout models suggest that GPR139 plays an anti-opioid role by modulating the signaling activity of the \u03bc-opioid receptor (MOR), as well as the intensity of withdrawal symptoms and nociception in behavioral paradigms. Modulation of GPR139 activity by surrogate agonists such as TAK-041 and JNJ-63533054 has shown promising results in experimental models; however, the use of TAK-041 in clinical trials has produced heterogeneous effects and has not met the intended primary endpoint. Here, we highlight current in vitro and in vivo studies of GPR139, its potential physiological roles, and therapeutic potential in the pathophysiology of neuropsychiatric and behavioral disorders. This review aims to focus on the current knowledge gaps to facilitate future studies that will contribute to the understanding of GPR139 as a therapeutic target for neuropsychiatric and behavioral disorders.\n                  <\/jats:p>","DOI":"10.1007\/s12035-025-04828-2","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T12:22:58Z","timestamp":1742300578000},"page":"9324-9337","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["GPR139, an Ancient Receptor and an Emerging Target for Neuropsychiatric and Behavioral Disorders"],"prefix":"10.1007","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8637-3155","authenticated-orcid":false,"given":"Minyu","family":"Chan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6664-4448","authenticated-orcid":false,"given":"Satoshi","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,18]]},"reference":[{"issue":"4","key":"4828_CR1","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/nrd2518","volume":"7","author":"MC Lagerstrom","year":"2008","unstructured":"Lagerstrom MC, Schioth HB (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. 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