{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T13:51:43Z","timestamp":1778593903017,"version":"3.51.4"},"reference-count":66,"publisher":"Cambridge University Press (CUP)","issue":"6","license":[{"start":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T00:00:00Z","timestamp":1566172800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/www.cambridge.org\/core\/terms"},{"start":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T00:00:00Z","timestamp":1564531200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/www.cambridge.org\/core\/terms"}],"content-domain":{"domain":["www.cambridge.org"],"crossmark-restriction":true},"short-container-title":["Acta Neuropsychiatr."],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec id=\"S0924270819000310_as1\"><jats:title>Objective:<\/jats:title><jats:p>Despite its numerous side effects, clozapine is still the most effective antipsychotics making it an ideal reference substance to validate the efficacy of novel compounds for the treatment of schizophrenia. However, blood\u2013brain barrier permeability for most new molecular entities is unknown, requiring central delivery. Thus, we performed a dose-finding study for chronic intracerebroventricular (icv) delivery of clozapine in mice.<\/jats:p><\/jats:sec><jats:sec id=\"S0924270819000310_as2\"><jats:title>Methods:<\/jats:title><jats:p>Specifically, we implanted wild-type C57BL\/6J mice with osmotic minipumps (Alzet) delivering clozapine at a rate of 0.15 \u00b5l\/h at different concentrations (0, 3.5, 7 and 14 mg\/ml, i.e. 0, 12.5, 25 and 50 \u00b5g\/day). Mice were tested weekly in a modified SHIRPA paradigm, for locomotor activity in the open field and for prepulse inhibition (PPI) of the acoustic startle response (ASR) for a period of 3 weeks.<\/jats:p><\/jats:sec><jats:sec id=\"S0924270819000310_as3\"><jats:title>Results:<\/jats:title><jats:p>None of the clozapine concentrations caused neurological deficits or evident gross behavioural alterations in the SHIRPA paradigm. In male mice, clozapine had no significant effect on locomotor activity or PPI of the ASR. In female mice, the 7 and 14 mg\/ml dose of clozapine significantly affected both open field activity and PPI, while 3.5 mg\/ml of clozapine increased PPI but had no effects on locomotor activity.<\/jats:p><\/jats:sec><jats:sec id=\"S0924270819000310_as4\"><jats:title>Conclusion:<\/jats:title><jats:p>Our findings indicate that 7 mg\/ml may be the optimal dose for chronic icv delivery of clozapine in mice, allowing comparison to screen for novel antipsychotic compounds.<\/jats:p><\/jats:sec>","DOI":"10.1017\/neu.2019.31","type":"journal-article","created":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T05:20:15Z","timestamp":1564550415000},"page":"305-315","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":2,"title":["Establishing an effective dose for chronic intracerebroventricular administration of clozapine in mice"],"prefix":"10.1017","volume":"31","author":[{"given":"Dilhan","family":"Esen-Sehir","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Courtney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Bittner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Reif","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1438-3850","authenticated-orcid":false,"given":"Florian","family":"Freudenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"56","published-online":{"date-parts":[[2019,8,19]]},"reference":[{"key":"S0924270819000310_ref65","doi-asserted-by":"publisher","DOI":"10.2174\/1874104501004020020"},{"key":"S0924270819000310_ref63","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2006.03.058"},{"key":"S0924270819000310_ref61","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/00004850-199801000-00003","article-title":"Co-administration of citalopram and clozapine: effect on plasma clozapine levels","volume":"13","author":"Taylor","year":"1998","journal-title":"International Clinical Psychopharmacology"},{"key":"S0924270819000310_ref58","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/S0893-133X(97)00110-3","article-title":"Discrepant findings of clozapine effects on prepulse inhibition of startle: is it the route or the rat","volume":"18","author":"Swerdlow","year":"1998","journal-title":"Neuropsychopharmacology"},{"key":"S0924270819000310_ref57","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/oxfordjournals.schbul.a033326","article-title":"Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia","volume":"24","author":"Swerdlow","year":"1998","journal-title":"Schizophrenia Bulletin"},{"key":"S0924270819000310_ref56","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2018.4489"},{"key":"S0924270819000310_ref55","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.ymgme.2018.05.003","article-title":"Best practices for the use of intracerebroventricular drug delivery devices","volume":"124","author":"Slavc","year":"2018","journal-title":"Molecular Genetics and Metabolism"},{"key":"S0924270819000310_ref54","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-002-1285-x"},{"key":"S0924270819000310_ref53","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/0006-3223(93)90059-M","article-title":"Test","volume":"34","author":"Schwarzkopf","year":"1993","journal-title":"Biological Psychiatry"},{"key":"S0924270819000310_ref52","first-page":"52932","article-title":"Implantation of miniosmotic pumps and delivery of tract tracers to study brain reorganization in pathophysiological conditions","volume":"107","author":"Sanchez-Mendoza","year":"2016","journal-title":"Journal of Visualized Experiments"},{"key":"S0924270819000310_ref66","doi-asserted-by":"publisher","DOI":"10.1007\/s003359900551"},{"key":"S0924270819000310_ref48","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.bbr.2009.04.021","article-title":"Prepulse inhibition and genetic mouse models of schizophrenia","volume":"204","author":"Powell","year":"2009","journal-title":"Behavioural Brain Research"},{"key":"S0924270819000310_ref46","volume-title":"Mouse Brain in Stereotaxic Coordinates","author":"Paxinos","year":"2001"},{"key":"S0924270819000310_ref45","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.2.1.3"},{"key":"S0924270819000310_ref44","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2010.02.008"},{"key":"S0924270819000310_ref43","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1095\/biolreprod27.2.327","article-title":"A longitudinal study of estrous cyclicity in aging C57BL\/6J mice: I. 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