{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T10:54:18Z","timestamp":1784804058939,"version":"3.55.0"},"reference-count":20,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T00:00:00Z","timestamp":1627862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100010173","name":"Smart Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010173","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Imbalance in the metabolic pathway linking excitatory and inhibitory neurotransmission has been implicated in multiple psychiatric and neurologic disorders. Recently, we described enantiomer\u2010specific effects of 2\u2010methylglutamate, which is not decarboxylated to the corresponding methyl analogue of gamma\u2010aminobutyric acid (GABA): 4\u2010aminopentanoic acid (4APA). Here, we tested the hypothesis that 4APA also has enantiomer\u2010specific actions in brain. Mouse cerebral synaptosome uptake (nmol\/mg protein over 30\u00a0min) of (<jats:italic>R<\/jats:italic>)\u20104APA or (<jats:italic>S<\/jats:italic>)\u20104APA was time and temperature dependent; however, the <jats:italic>R<\/jats:italic> enantiomer had greater uptake, reduction of endogenous GABA concentration, and release following membrane depolarization than did the <jats:italic>S<\/jats:italic> enantiomer. (<jats:italic>S<\/jats:italic>)\u20104APA exhibited some weak agonist (GABA<jats:sub>A<\/jats:sub> \u03b14\u03b23\u03b4, GABA<jats:sub>A<\/jats:sub> \u03b15\u03b22\u03b32, and GABA<jats:sub>B<\/jats:sub> B1\/B2) and antagonist (GABA<jats:sub>A<\/jats:sub> \u03b16\u03b22\u03b32) activity while (<jats:italic>R<\/jats:italic>)\u20104APA showed weak agonist activity only with GABAA \u03b15\u03b22\u03b32. Both 4APA enantiomers (100\u00a0mg\/kg IP) were detected in mouse brain 10\u00a0min after injection, and by 1\u00a0hr had reached concentrations that were stable over 6\u00a0hr; both enantiomers were cleared rapidly from mouse serum over 6\u00a0hr. Two\u2010month\u2010old mice had no mortality following 100\u2013900\u00a0mg\/kg IP of each 4APA enantiomer but did have similar dose\u2010dependent reduction in distance moved in a novel cage. Neither enantiomer at 30 or 100\u00a0mg\/kg impacted outcomes in 23 measures of well\u2010being, activity chamber, or withdrawal from hot plate. Our results suggest that enantiomers of 4APA are active in mouse brain, and that (<jats:italic>R<\/jats:italic>)\u20104APA may act as a novel false neurotransmitter of GABA. Future work will focus on disease models and on possible applications as neuroimaging agents.<\/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\/jnc15474-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15474","type":"journal-article","created":{"date-parts":[[2021,7,17]],"date-time":"2021-07-17T17:45:24Z","timestamp":1626543924000},"page":"1074-1082","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enantiomers of 4\u2010aminopentanoic acid act as false GABAergic neurotransmitters and impact mouse behavior"],"prefix":"10.1111","volume":"158","author":[{"given":"Adam M.","family":"Wawro","sequence":"first","affiliation":[{"name":"Department of Pathology Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandresh R.","family":"Gajera","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Le\u015bniak","sequence":"additional","affiliation":[{"name":"ChEM\u2010H Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2110-8363","authenticated-orcid":false,"given":"Kathleen S.","family":"Montine","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curt R.","family":"Fischer","sequence":"additional","affiliation":[{"name":"ChEM\u2010H Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nay L.","family":"Saw","sequence":"additional","affiliation":[{"name":"Behavioral and Functional Neuroscience Laboratory Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrdad","family":"Shamloo","sequence":"additional","affiliation":[{"name":"Behavioral and Functional Neuroscience Laboratory Stanford University Stanford CA USA"},{"name":"Department of Neurosurgery Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Montine","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.03913.x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(83)90630-5"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.289.6438.156"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tplants.2004.01.006"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1982.tb05348.x"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0891-0618(92)90026-M"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2018.11.008"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050456"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.08.040168.002113"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0197-0186(85)90041-5"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6CY01625A"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1246\/bcsj.52.2670"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00158a052"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197211162872005"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.03.036"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.6.5_Pt_2.II45"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(01)01885-7"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2018.2941"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1039\/JR9550001626"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-87569-1"}],"container-title":["Journal 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