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Perturbation of the D2R system may influence an individual's response to alcohol. Alternative splicing of the D2R gene generates two isoforms: D2 long form (D2L) and D2 short form (D2S). It is unclear whether differences in the expression of D2L and D2S influence alcohol's effects. Here we examined if altered expression levels of either D2R isoform would influence alcohol effects on reward\u2010related behaviour and relevant signalling pathways using knockout (KO) mice expressing either D2R isoform. We found that D2L KO mice (expressing only D2S) displayed a strong alcohol conditioned place preference (CPP) compared to WT mice and D2S KO mice (expressing only D2L). Alcohol exposure caused a downregulation of cannabinoid 1 receptors (CB1R) expression but an upregulation of cannabinoid 2 receptors (CB2R) expression in the striatum of D2L KO mice but not in WT and D2S KO mice. In addition, alcohol exposure resulted in decreased Akt phosphorylation selectively in D2L KO mice. Furthermore, the gene expressions of tyrosine hydroxylase (TH), Arc and RETN were also selectively downregulated in D2L KO mice following chronic alcohol exposure. Our results indicated that an alteration in the expression of D2S vs. D2L had significant impacts on alcohol\u2010induced reward and gene expression changes in the striatum. These findings suggest that the increased expression level of D2S to D2L may be a pathophysiological mechanism for developing alcoholism, possibly through triggering a cascade of changes in the cannabinoid\u2010Akt signalling pathway and relevant signalling network.<\/jats:p>","DOI":"10.1111\/adb.70093","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T09:56:20Z","timestamp":1763200580000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dopamine D2S\/D2L Receptor Regulation of Alcohol\u2010Induced Reward and Signalling"],"prefix":"10.1111","volume":"30","author":[{"given":"Mohd","family":"Tayyab","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Biology The University of Texas at Tyler School of Medicine  Tyler Texas USA"},{"name":"Department of Pharmaceutical Sciences and Health Outcome The University of Texas at Tyler Fisch College of Pharmacy  Tyler Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshikuni","family":"Sasaoka","sequence":"additional","affiliation":[{"name":"Department of Comparative and Experimental Medicine, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Animal Model Development, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nae","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Comparative and Experimental Medicine, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8091-8879","authenticated-orcid":false,"given":"Kenji","family":"Sakimura","sequence":"additional","affiliation":[{"name":"Department of Animal Model Development, Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anetta","family":"Ninan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Health Outcome The University of Texas at Tyler Fisch College of Pharmacy  Tyler Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8350-9926","authenticated-orcid":false,"given":"YanYan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology The University of Texas at Tyler School of Medicine  Tyler Texas USA"},{"name":"Department of Pharmaceutical Sciences and Health Outcome The University of Texas at Tyler Fisch College of Pharmacy  Tyler Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcna.2021.08.003"},{"key":"e_1_2_11_3_1","unstructured":"SAMHSA 2022NSDUH Annual National Report. 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