Central administration of histamine H1 receptor agonist, fMPH, blocks olanzapineinduced activation of ampk-cpt1 signaling in the dorsal vagal complex in rats
Olanzapine treatment is associated with severe obesity. The AMPactivated protein kinase (AMPK) in the dorsal vagal complex (DVC) plays an important role in feeding regulation, which can regulate energy balance through modulating acetyl-CoA carboxylase (ACC)-carnitine palmitoyltransferase 1 (CPT1) signaling. Histamine H1 receptor (H1R) antagonism acts as a key contributor for olanzapine-induced obesity. Aim: To investigate the effect of olanzapine on food intake and DVC AMPK-CPT1 signaling, and whether these effects could be blocked by central H1R activation. Methods: Rats were treated with olanzapine (1 mg/kg, t.i.d., orally, n=5-8/group) or vehicle for 4 days. On day 5th, different doses (200nM or 100nM) of 2-(3-trifluoromethylphenyl) histamine (FMPH, H1R agonist), or saline was centrally injected before olanzapine or vehicle was given. Cumulative food intake was measured. After 3 days drug wash out period, the treatment was repeated and rats were sacrificed, and DVC tissues were collected for the detection of phosphor-AMPK, phosphor-ACC levels and CPT1 activity. Results: Olanzapine-induced hyperphagia after 4 days treatment was significantly reduced by FMPH in a dose-dependent manner up to 16hrs (p
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