Protein level alteration of endocannabinoid system components after chronic, oral self-administration of three second-generation antipsychotics in rat

Objective: Second-generation antipsychotics (SGAs) often cause metabolic adverse effects (mAE) such as weight gain, and dyslipidemia. The mechanisms underlying SGA induced mAE are not fully elucidated. The endocannabinoid system (ECS) is a critical system in the regulation of energy metabolism that may be involved in SGA induced mAE. In the present experiment, we studied the expression of three major components of ECS: cannabinoid receptor 1 (CB1), fatty acid amidohydrolase (FAAH) and monoacyl glycerol lipase (MAGL) after chronic administration in rat of three SGAs: olanzapine (Ola), aripiprazole (Ari) and cariprazine (Car). Methods: Drugs were self-administered orally, in two doses by female, adult Wistar white rats (n=6 per treatment group) for six weeks. After the treatment period, the animals were sacrificed, and visceral (perirenal) white fat pads were collected. The fat tissue samples were homogenized, and the expression level of CB1, FAAH and MAGL were compared by western-blot analysis. Results: CB1 expression was noticeably increased after the low-dose Ola treatment, although not statistically significant. All three drugs augmented the FAAH expression, the effect being significant after the treatment with low-dose Car. The expression of MAGL was not influenced significantly by the three SGAs; nevertheless, an increasing tendency can be remarked in the case of Ari and Car. Conclusions: Promoting the CB1 expression in adipose tissue could contribute to weight increasing and other mAE effects of Ola. The tendency of Ari and Car to enhance the breakdown enzymes expression might have some role in more favourable mAE of these drugs.