{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T02:54:11Z","timestamp":1791255251413,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,30]]},"group-title":"Neuroscience","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R00AA027835"],"award-info":[{"award-number":["R00AA027835"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P20GM130422"],"award-info":[{"award-number":["P20GM130422"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Alcohol use disorders are heritable, and large-scale genome-wide association studies have recently identified novel genetic loci that are correlated with alcohol consumption and problematic alcohol use. One such gene is\n                  <jats:italic>Slc39a8<\/jats:italic>\n                  , which encodes the ion transporter ZIP8, responsible for cellular import of zinc and other metals.\n                  <jats:italic>Slc39a8<\/jats:italic>\n                  is highly pleiotropic, and a common missense variant has been associated with decreased problematic alcohol use. Here, we used\n                  <jats:italic>Slc39a8<\/jats:italic>\n                  heterozygous (HET) knockout mice and their wild type (WT) littermates to characterize the effects of reduced gene function on two models of voluntary alcohol consumption (drinking in the dark and intermittent access two-bottle choice), and anxiety- and depression-like behavior. We found that HET mice consumed less alcohol than WT in the intermittent access two-bottle choice procedure. No evidence was found for genotypic differences in baseline locomotor activity, anxiety-like, or depression-like behavior in the open field and forced swim tests.\n                  <jats:italic>Slc39a8<\/jats:italic>\n                  mRNA expression and alcohol metabolism experiments confirmed decreased brain expression of\n                  <jats:italic>Slc39a8<\/jats:italic>\n                  in HET mice and unchanged alcohol metabolism. Basal and post-alcohol measurement of zinc levels showed that HET mice after ethanol exposure had lower zinc concentrations in the liver and higher concentrations in blood than WT animals. Analysis of the spatial distribution of multiple trace metals in the brains of na\u00efve\n                  <jats:italic>Slc39a8<\/jats:italic>\n                  HET and WT mice using Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) showed region-specific genotypic differences in levels of zinc and iron. These results provide evidence for a direct role of\n                  <jats:italic>Slc39a8<\/jats:italic>\n                  in ethanol consummatory behavior that does not appear to be due to metabolism, affective state, or locomotor activity. Moreover, we confirm that this animal model shows tissue- and brain region-specific alterations in zinc levels, highlighting potential mechanisms for future study.\n                <\/jats:p>","DOI":"10.64898\/2026.09.24.754187","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:30:13Z","timestamp":1790803813000},"source":"Crossref","is-referenced-by-count":0,"title":["Functional validation and characterization of\n                  <i>Slc39a8<\/i>\n                  genotype effects on ethanol consumption and related phenotypes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7134-8370","authenticated-orcid":false,"given":"Andr\u00e9 Lucas","family":"Silva-Borges","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna-Jael G.","family":"Paredes","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebeka","family":"Sultana","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia G.","family":"Pareja","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3722-7578","authenticated-orcid":false,"given":"Amanda 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