title: Olanzapine-activated AMPK signaling in the dorsal vagal complex is attenuated by histamine H1 receptor agonist in female rats.
abstract: Weight gain and its related metabolic disorders are major side effects associated with second generation antipsychotic drug treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of olanzapine treatment (8, 16, and 36 d) on DVC AMPK signaling in olanzapine-induced weight gain and whether these changes are associated with olanzapine-induced H1 receptor antagonism. During the 8-day olanzapine treatment, the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK (pAMPK) (activated AMPK) as well as its directly downstream phospho-acetyl-coenzyme A carboxylase was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36 d of olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1 receptor protein expression was not significantly altered by olanzapine, the pAMPK expression was significantly positively correlated with the H1 receptor level after the 8-, 16-, and 36-day olanzapine treatments. Moreover, we showed that an H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in olanzapine-induced obesity. Thus, olanzapine-induced DVC AMPK activation may be at least partially related to olanzapine's antagonistic effect on the H1 receptor.
authors.affiliation: Centre for Translational Neuroscience (M.H., Q.Z., C.D., H.W., X.-F.H.), School of Medicine and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522, New South Wales, Australia; and Schizophrenia Research Institute (C.D., X.-F.H.), Darlinghurst 2010, New South Wales, Australia.
authors.forename: Meng
authors.initials: M
authors.lastname: He
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.forename: Hongqin
authors.initials: H
authors.lastname: Wang
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects*; D001835:Body Weight / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D017442:Histamine Agonists; D006963:Hyperphagia / Q000139:chemically induced; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced*; D000077152:Olanzapine; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D017442:Histamine Agonists; D011969:Receptors, Histamine H1; D001569:Benzodiazepines; D055372:AMP-Activated Protein Kinases; D000077152:Olanzapine