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To probe the effects of ASC deficiency and AD pathology on the DAergic system, gulo<jats:sup>\u2013\/\u2013<\/jats:sup> mice, which like humans depend on dietary ASC to maintain adequate tissue levels, were crossed with APP\/PSEN1 mice and provided sufficient or depleted ASC supplementation from weaning until 12\u00a0months of age. Ex vivo fast\u2010scan cyclic voltammetry showed that chronic ASC depletion and APP\/PSEN1 genotype both independently decreased dopamine release in the nucleus accumbens, a hub for motivational behavior and reward, while DA clearance was similar across all groups. In striatal tissue containing nucleus accumbens, low ASC treatment led to decreased levels of DA and its metabolites 3,4\u2010dihydroxyohenyl\u2010acetic acid (DOPAC), 3\u2010methoxytyramine (3\u2010MT), and homovanillic acid (HVA). Decreased enzyme activity observed through lower pTH\/TH ratio was driven by a cumulative effect of ASC depletion and APP\/PSEN1 genotype. Together the data show that deficits in dopaminergic neurotransmission resulting from age and disease status are magnified in conditions of low ASC which decrease DA availability during synaptic transmission. Such deficits may contribute to the non\u2010cognitive behavioral changes observed in AD including decreased motivation, anhedonia, and sleep disorders.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15151-fig-0005-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15151","type":"journal-article","created":{"date-parts":[[2020,8,15]],"date-time":"2020-08-15T07:12:53Z","timestamp":1597475573000},"page":"656-665","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Ascorbate deficiency decreases dopamine release in gulo<sup>\u2013\/\u2013<\/sup> and APP\/PSEN1 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