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To elucidate the process whereby acetylcholine (ACh) release is maintained and regulated in the central nervous system, uptake of [<jats:sup>3<\/jats:sup>H]choline and subsequent synthesis and release of [<jats:sup>3<\/jats:sup>H]ACh were investigated in rat striatal segments. Incubation with [<jats:sup>3<\/jats:sup>H]choline elicited efficient uptake via high\u2010affinity choline transporter\u20101, resulting in accumulation of [<jats:sup>3<\/jats:sup>H]choline and [<jats:sup>3<\/jats:sup>H]ACh. However, following inhibition of ACh esterase (AChE), incubation with [<jats:sup>3<\/jats:sup>H]choline led predominantly to the accumulation of [<jats:sup>3<\/jats:sup>H]ACh. Electrical stimulation and KCl depolarization selectively released [<jats:sup>3<\/jats:sup>H]ACh but not [<jats:sup>3<\/jats:sup>H]choline. [<jats:sup>3<\/jats:sup>H]ACh release gradually declined upon repetitive stimulation, whereas the release was reproducible under inhibition of AChE. [<jats:sup>3<\/jats:sup>H]ACh release was abolished after treatment with vesamicol, an inhibitor of vesicular ACh transporter. These results suggest that releasable ACh is continually replenished from the cytosol to releasable pools of cholinergic vesicles to maintain cholinergic transmission. [<jats:sup>3<\/jats:sup>H]ACh release evoked by electrical stimulation was abolished by tetrodotoxin, but that induced by KCl was largely resistant. ACh release was Ca<jats:sup>2+<\/jats:sup> dependent and exhibited slightly different sensitivities to N\u2010 and P\u2010type Ca<jats:sup>2+<\/jats:sup> channel toxins (\u03c9\u2010conotoxin GVIA and \u03c9\u2010agatoxin IVA, respectively) between both stimuli. [<jats:sup>3<\/jats:sup>H]ACh release was negatively regulated by M2 muscarinic and D2 dopaminergic receptors. The present results suggest that inhibition of AChE within cholinergic neurons and of presynaptic negative regulation of ACh release contributes to maintenance and facilitation of cholinergic transmission, providing a potentially useful clue for the development of therapies for cholinergic dysfunction\u2010associated disorders, in addition to inhibition of synaptic cleft AChE.<\/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\/jnc15556-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15556","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T15:03:39Z","timestamp":1638975819000},"page":"342-355","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Evaluation of radiolabeled acetylcholine synthesis and release in rat striatum"],"prefix":"10.1111","volume":"160","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6881-5391","authenticated-orcid":false,"given":"Ikunobu","family":"Muramatsu","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Medicine Kanazawa Medical University  Uchinada Ishikawa Japan"},{"name":"Division of Genomic Science and Microbiology School of Medicine University of Fukui  Eiheiji Fukui Japan"},{"name":"Kimura Hospital  Awara Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junsuke","family":"Uwada","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine Kanazawa Medical University  Uchinada Ishikawa Japan"},{"name":"Division of Cellular Signal Transduction Department of Biochemistry Asahikawa Medical University  Asahikawa Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyasu","family":"Chihara","sequence":"additional","affiliation":[{"name":"Division of Genomic Science and Microbiology School of Medicine University of Fukui  Eiheiji Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyonao","family":"Sada","sequence":"additional","affiliation":[{"name":"Division of Genomic Science and Microbiology School of Medicine University of Fukui  Eiheiji Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao\u2010Hsien","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Genomic Science and Microbiology School of Medicine University of Fukui  Eiheiji Fukui Japan"},{"name":"Department of Anesthesia En Chu Kon Hospital  New Taipei City Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Yazawa","sequence":"additional","affiliation":[{"name":"Division of Cellular Signal Transduction Department of Biochemistry Asahikawa Medical University  Asahikawa Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanobu","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Division of Cellular Signal Transduction Department of Biochemistry Asahikawa Medical University  Asahikawa Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaharu","family":"Ishibashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine Kanazawa Medical University  Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Masuoka","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine Kanazawa Medical University  Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002210050858"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2858-3_12"},{"key":"e_1_2_10_4_1","first-page":"48","article-title":"Pharmacological characterization of the acetylcholine transport system in purified Torpedo electric organ synaptic vesicles","volume":"24","author":"Anderson D. 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