A ganglionic blocker and adrenoceptor ligands modify clozapine-induced insulin resistance.

Autor: Yuen JWY; Faculty of Medicine, Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Wu C; Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver V6T 1Z3, BC, Canada., Wang CK; Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver V6T 1Z3, BC, Canada., Kim DD; Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver V6T 1Z3, BC, Canada., Procyshyn RM; Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada., Panenka WG; Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada., Honer WG; Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada., Barr AM; Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver V6T 1Z3, BC, Canada. Electronic address: al.barr@ubc.ca.
Jazyk: angličtina
Zdroj: Psychoneuroendocrinology [Psychoneuroendocrinology] 2021 Jul; Vol. 129, pp. 105257. Date of Electronic Publication: 2021 May 12.
DOI: 10.1016/j.psyneuen.2021.105257
Abstrakt: Clozapine is a second generation antipsychotic drug that has proven to be helpful in the management of patients with psychotic disorders that are resistant to other medications. Unfortunately, the majority of patients treated with clozapine develop metabolic dysregulation, including weight gain and insulin resistance. There are few treatments available to effectively counter these side-effects. The goal of the present study was to use an established animal model to better understand the nature of these metabolic side-effects and determine whether existing drugs could be used to alleviate metabolic changes. Adult female rats were treated with a range of doses of clozapine (2, 10 and 20 mg/kg) and subjected to the hyperinsulinemic-euglycemic clamp, to measure whole-body insulin resistance. Clozapine dose-dependently decreased the glucose infusion rate, reflecting pronounced insulin resistance. To reverse the insulin resistance, rats were co-treated with the ganglionic blocker mecamylamine (0.1, 1.0 and 5.0 mg/kg) which dose-dependently reversed the effects of 10 mg/kg clozapine. A 1.0 mg/kg dose of mecamylamine independently reversed the large increase in peripheral epinephrine caused by treatment with clozapine. To study the influence of specific adrenoceptors, rats were treated with multiple doses of α 1 (prazosin), α 2 (idazoxan), β 1 (atenolol) and β 2 (butoxamine) adrenoceptor antagonists after the onset of clozapine-induced insulin resistance. Both beta blockers were effective in attenuating the effects of clozapine, while idazoxan had a smaller effect; no change was seen with prazosin. The current results indicate that peripheral catecholamines may play a role in clozapine's metabolic effects and be a target for future treatments.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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