Acute cardiometabolic side effects of clozapine in rodents
department or school: Medicine, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Yuen, Jessica Wing Yee
issued: 2022-05-31T07:00:00Z
issued: 2020
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Clozapine (CLZ) is considered the treatment of choice for treatment resistant schizophrenia. Although highly efficacious, the widespread use of CLZ is limited by metabolic side effects, fatal agranulocytosis and cardiovascular complications such as myocarditis via unknown mechanisms. As the autonomic nervous system (ANS) is known to regulate metabolic and cardiovascular function, we sought to assess the involvement of the ANS in the cardiometabolic effects of CLZ in rodent models. Glucose dysregulation from acute CLZ treatment was evaluated using the hyperinsulinemic euglycemic clamp (HIEC) and the intraperitoneal glucose tolerance test (IGTT). Plasma catecholamine (CAT) levels were measured using high performance liquid chromatography (HPLC) to determine autonomic activity. We also assessed the metabolic liability of the principal metabolite of CLZ, norclozapine (NOR), and compared the results to its parent compound. In a separate series of experiments, we measured cardiovascular parameters in response to CLZ in a novel rodent model of CLZ-induced tachycardia. We attempted to reverse CLZ-induced tachycardia with mecamylamine (MEC), a ganglionic blocker, and propranolol (PRO), a β-adrenoceptor blocker. Lastly, we performed a study to evaluate the use of adrenoceptor ligands in treating CLZ-induced glucose dysregulation. Our results indicate NOR does not induce metabolic dysregulation at the same severity as CLZ, despite substantial retention of NOR in plasma. NOR induced insulin resistance but not glucose intolerance at the highest dose compared to vehicle. CLZ induced tachycardia and depressor effects immediately following injection. MEC and PRO reversed the tachycardia, where MEC caused significant depressor effects. The effects were not noted with PRO. There was a significant elevation in plasma NE levels from CLZ treatment which was reversible with MEC. Our pilot study showed β-adrenoceptor blockers reversed insulin resistance associated with CLZ, whereas α-adre…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/74443
note: i ACUTE CARDIOMETABOLIC SIDE EFFECTS OF CLOZAPINE IN RODENTS by JESSICA WING YEE YUEN B.Sc., The University of British Columbia, 2006 M.Med.Sci, The University of Hong Kong, 2009 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Neuroscience) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2020 © Jessica Wing Yee Yuen, 2020 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Acute cardiometabolic side effects of clozapine in rodents submitted by Jessica Wing Yee Yuen in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Neuroscience Examining Committee: Dr. Alasdair Barr, Associate Professor, Department of Anesthesiology, Pharmacology & Therapeutics, UBC Supervisor Dr. Ric Procyshyn, Clinical Professor, Department of Psychiatry, UBC Supervisory Committee Member Dr. Victor Viau, Professor, Department of Cellular & Physiological Sciences, UBC University Examiner Dr. Susanne Clee, Assistant Professor, Department of Cellular & Physiological Sciences, UBC University Examiner Additional Supervisory Committee Members: Dr. Catherine Pang, Professor, Department of Anesthesiology, Pharmacology & Therapeutics, UBC Supervisory Committee Member Dr. William Panenka, Assistant Professor, Department of Psychiatry, UBC Supervisory Committee Member iii Abstract Clozapine (CLZ) is considered the treatment of choice for treatment resistant schizophrenia. Although highly efficacious, the widespread use of CLZ is limited by metabolic side effects, fatal agranulocytosis and cardiovascular complications such as myocarditis via unknown mechanisms. As the autonomic nervous system (ANS) is known to regulate metabolic and cardiovascular function, we sought to assess the involvement of the ANS in the cardiometabolic effects of CLZ in rodent mod…
has type: Thesis/Dissertation
date issued: 2020-11
is shown at: 10.14288/1.0390492
language: eng
degree discipline: Neuroscience
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/74443