title: Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.
abstract: Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered. The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance. In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant. Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine. Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.
authors.affiliation: Kemotech Srl, Edificio 3, Località Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Lazzari
authors.affiliation: Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Scientific and Technological Park of Sardinia - Polaris, Pula, CA, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Serra
authors.affiliation: Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Scientific and Technological Park of Sardinia - Polaris, Pula, CA, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marcello
authors.affiliation: Kemotech Srl, Edificio 3, Località Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pira
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Scientific and Technological Park of Sardinia - Polaris, Pula, CA, Italy. Electronic address: amastinu@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Mastinu
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects*; D001584:Benzoxepins / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004359:Drug Therapy, Combination; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005260:Female; D000077152:Olanzapine; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D015430:Weight Gain / Q000187:drug effects* / Q000502:physiology
chemical_list: C586703:8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta(1,2-c)pyrazole-3-carboxamide; D014150:Antipsychotic Agents; D001584:Benzoxepins; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D001569:Benzodiazepines; D000077152:Olanzapine
keywords: Animal behaviour; CB1 receptor; Metabolic enzymes; Olanzapine; Weight gain