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However, previous studies have revealed that peripherally injected CNO is reverse-metabolized into clozapine, which, in addition to activating DREADDs, acts as an antagonist at various neurotransmitter receptors, suggesting potential off-target effects of CNO on animal physiology and behaviors. Recently, second-generation DREADD agonists compound 21 (C21) and JHU37160 (J60) have been developed, but their off-target effects are not fully understood.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Objectives<\/jats:title>\n                <jats:p>The present studies assessed the effect of novel DREADD ligands on reward-seeking behavior.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We first tested the possible effect of acute i.p. injection of low-to-moderate (0.1, 0.3, 1, 3 mg\/kg) of CNO, C21, and J60 on motivated reward-seeking behavior in wild-type mice. We then examined whether a high dose (10 mg\/kg) of these drugs might be able to alter responding.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Low-to-moderate doses of all drugs and a high dose of CNO or C21 did not alter operant lick responding for a reward under a progressive ratio schedule of reinforcement, in which the number of operant lick responses to obtain a reward increases after each reward collection. However, high-dose J60 resulted in a total lack of responding that was later observed in an open field arena to be due to a sedative effect.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study provides definitive evidence that commonly used doses of CNO, C21, and J60 have negligible off-target effects on motivated reward-seeking but urges caution when using high doses of J60 due to sedative effects.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00213-023-06465-w","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T09:02:22Z","timestamp":1696410142000},"page":"89-96","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Clozapine N-oxide, compound 21, and JHU37160 do not influence effortful reward-seeking behavior in mice"],"prefix":"10.1007","volume":"241","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1569-8207","authenticated-orcid":false,"given":"Yoshiatsu","family":"Aomine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1252-2731","authenticated-orcid":false,"given":"Yoshinobu","family":"Oyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6952-7749","authenticated-orcid":false,"given":"Koki","family":"Sakurai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0250-1146","authenticated-orcid":false,"given":"Tom","family":"Macpherson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3633-7062","authenticated-orcid":false,"given":"Takaaki","family":"Ozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8653-311X","authenticated-orcid":false,"given":"Takatoshi","family":"Hikida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"key":"6465_CR1","doi-asserted-by":"publisher","unstructured":"Aomine Y, Sakurai K, Macpherson T, Ozawa T, Miyamoto Y, Yoneda Y, Oka M, Hikida T (2022) Importin \u03b13 (KPNA3) deficiency augments effortful reward-seeking behavior in mice. 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