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Here, we investigated regulatory mechanisms for acetylcholine (AC<\/jats:styled-content>h) release from cholinergic neurons by performing superfusion experiments with rat striatal segments after labelling the cellular AC<\/jats:styled-content>h pool with [3<\/jats:sup>H]choline. Electrical stimulation\u2010evoked pronounced [3<\/jats:sup>H]AC<\/jats:styled-content>h release from cholinergic neurons. The estimated quantity of [3<\/jats:sup>H]AC<\/jats:styled-content>h release per pulse of electrical stimulation was reduced by an increase in stimulus frequency, showing an inverse correlation between release probability of AC<\/jats:styled-content>h and neuronal excitation. AC<\/jats:styled-content>h release was also negatively regulated by pre\u2010synaptic muscarinic AC<\/jats:styled-content>h receptors (mAChR<\/jats:styled-content>s). The autoinhibition induced by released AC<\/jats:styled-content>h was predominantly suppressed by the M2<\/jats:sub>\u2010selective antagonist AF<\/jats:styled-content>\u2010DX<\/jats:styled-content> 116, partially inhibited by M3<\/jats:sub>\u2010selective darifenacin, and minimally by M4<\/jats:sub>\u2010selective PD<\/jats:styled-content> 102807. Other subtype\u2010selective antagonists had no effect at subtype\u2010selective concentrations. AC<\/jats:styled-content>h esterase (AC<\/jats:styled-content>hE) inhibitors (diisopropylfluorophosphate, donepezil and galantamine) at concentrations that mostly inhibit esterase activity reduced [3<\/jats:sup>H]AC<\/jats:styled-content>h release, and the reduction was abolished by treatment with atropine. This implies that pre\u2010synaptic autoreceptors are activated more after blockade of AC<\/jats:styled-content>h hydrolysis, leading to autoinhibition of AC<\/jats:styled-content>h release and consequent reduction in synaptic AC<\/jats:styled-content>h concentrations. [3<\/jats:sup>H]efflux was also enhanced by AC<\/jats:styled-content>h uptake inhibitors (100\u00a0\u03bcM hemicholinium\u20103 and physostigmine), regardless of AC<\/jats:styled-content>h hydrolysis. This study shows that synaptic AC<\/jats:styled-content>h concentrations in striatal cholinergic neurons are regulated in a complex manner by many factors such as release probability, pre\u2010synaptic M2<\/jats:sub>\/M3<\/jats:sub>\/M4<\/jats:sub> mAChR<\/jats:styled-content>s, AC<\/jats:styled-content>hE and post\u2010synaptic AC<\/jats:styled-content>h uptake, and provides important information about cholinergic neurotransmission for future exploration of therapeutic strategies for Alzheimer's and other central nervous system diseases.<\/jats:p><\/jats:sec>Open science badges<\/jats:title><\/jats:p>This article has received a badge for *Open Materials<\/jats:bold>* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https:\/\/cos.io\/our-services\/openscience-badges\/<\/jats:ext-link>.<\/jats:p><\/jats:sec>\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14701","type":"journal-article","created":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T11:15:48Z","timestamp":1554894948000},"page":"605-623","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Novel regulatory systems for acetylcholine release in rat striatum and anti\u2010Alzheimer's disease drugs"],"prefix":"10.1111","volume":"149","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":"Division of Cellular Signal Transduction Department of Biochemistry Asahikawa Medical University Asahikawa Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatsumi","family":"Yoshiki","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":"Kung\u2010Shing","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Genomic Science and Microbiology School of Medicine University of Fukui Eiheiji Fukui Japan"},{"name":"Department of Surgery Kaohsiung Medical University Kaohsiung Taiwan"}],"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":"Matomo","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine Kanazawa Medical University Uchinada, Ishikawa 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":[[2019,5,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002210050858"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2858-3_12"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0047-6374(01)00314-1"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2013.07.004"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12306"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1988.tb02497.x"},{"key":"e_1_2_7_8_1","first-page":"273","article-title":"Identification of the primary muscarinic autoreceptor subtype in rat striatum as m2 through a correlation of in\u00a0vivo microdyalysis and in\u00a0vitro receptor binding data","volume":"273","author":"Billard W.","year":"1995","journal-title":"J. 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