Betahistine ameliorates olanzapine-induced weight gain through modulation of histaminergic, NPY and AMPK pathways.

Abstract

Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of olanzapine and betahistine (O+B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O+B co-treatment significantly downregulated the H1R levels, compared to the olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by olanzapine, but it was significantly reversed by O+B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio, compared with olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although olanzapine administration decreased the POMC mRNA level, this level was not affected by O+B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.

• Authors: Jiamei Lian, Xu-Feng Huang, Nagesh Pai, Chao Deng
• Journal: Psychoneuroendocrinology (Psychoneuroendocrinology) Vol. 48 Pg. 77-86 (Oct 2014) ISSN: 1873-3360 [Electronic] England
• PMID: 24992721 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antipsychotic Agents
• Histamine Agonists
• Neuropeptide Y
• Benzodiazepines
• Histamine
• Adenylate Kinase
• Olanzapine
• Betahistine

Topics

• Adenylate Kinase (metabolism)
• Adiposity (drug effects)
• Animals
• Antipsychotic Agents (adverse effects)
• Benzodiazepines (adverse effects)
• Betahistine (pharmacology)
• Eating (drug effects)
• Female
• Histamine (metabolism)
• Histamine Agonists (pharmacology)
• Neuropeptide Y (metabolism)
• Olanzapine
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Weight Gain (drug effects)