{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T04:05:36Z","timestamp":1793505936359,"version":"4.5.0"},"reference-count":185,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PeakLogic Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Autism spectrum disorder (ASD) is primarily characterized by core deficits in social skills, communication, and cognition and by repetitive stereotyped behaviors. These manifestations are variable between individuals, and ASD pathogenesis is complex, with over a thousand implicated genes, many epigenetic factors, and multiple environmental influences. The mesolimbic dopamine (DA) mediated brain reward system is held to play a key role, but the rapidly expanding literature reveals intricate, nuanced signaling involving a wide array of mesolimbic loci, neurotransmitters and receptor subtypes, and neuronal variants. How altered DA signaling may constitute a downstream convergence of the manifold causal origins of ASD is not well understood. A clear working framework of ASD pathogenesis may help delineate common stages and potential diagnostic and interventional opportunities. Hence, we summarize the known natural history of ASD in the context of emerging data and perspectives to update ASD reward signaling. Then, against this backdrop, we proffer a provisional framework that organizes ASD pathogenesis into successive levels, including (1) genetic and epigenetic changes, (2) disrupted mesolimbic reward signaling pathways, (3) dysregulated neurotransmitter\/DA signaling, and finally, (4) altered neurocognitive and social behavior and possible antagonist\/agonist based ASD interventions. This subdivision of ASD into a logical progression of potentially addressable parts may help facilitate the rational formulation of diagnostics and targeted treatments.<\/jats:p>","DOI":"10.3390\/brainsci14070733","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T07:57:23Z","timestamp":1721721443000},"page":"733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Dopamine Dysregulation in Reward and Autism Spectrum Disorder"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6727-803X","authenticated-orcid":false,"given":"Kenneth","family":"Blum","sequence":"first","affiliation":[{"name":"Division of Addiction Research & Education, Center for Exercise Sports, Mental Health, Western University of Health Sciences, Pomona, CA 91766, USA"},{"name":"Sunder Foundation, Palm Springs, CA 92264, USA"},{"name":"Division of Personalized Neuromodulations, PeakLogic, LLC, Del Mar, CA 92130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8185-0688","authenticated-orcid":false,"given":"Abdalla","family":"Bowirrat","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel 40700, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keerthy","family":"Sunder","sequence":"additional","affiliation":[{"name":"Sunder Foundation, Palm Springs, CA 92264, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panayotis K.","family":"Thanos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, State University of New York, SUNY, Buffalo, NY 14215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, State University of New York, SUNY, Buffalo, NY 14215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine A.","family":"Dennen","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA 19145, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Elman","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Harvard University School of Medicine, Cambridge, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin T.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Division of Personalized Neuromodulations, PeakLogic, LLC, Del Mar, CA 92130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0507-5883","authenticated-orcid":false,"given":"Milan T.","family":"Makale","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1159\/000478725","article-title":"A Dopamine Hypothesis of Autism Spectrum Disorder","volume":"39","year":"2017","journal-title":"Dev. 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