Objectives: 

Antipsychotic drugs (APDs) represent a cornerstone in the treatment of schizophrenia. However, several APDs induce metabolic adverse effects like weight gain, dyslipidemia and diabetes type 2. We and others have demonstrated that APDs activate de novo lipid biosynthesis in cultured cell lines and in peripheral tissues from rats via activation of the SREBP transcription factors. Interestingly, antipsychotic drugs have also been demonstrated to induce alteration in fatty acid metabolism in the hypothalamus. Activation of AMP-activated protein kinase (AMPK) has been suggested to be relevant for APD-associated hyperphagia, but the findings are ambiguous. To further investigate the role of AMPK activation in the hyperphagic effects of OLZ, we here explored the effect of dominant negative (DN) AMPK targeting the arcuate nucleus of the hypothalamus (ARC) in a rodent model for OLZ-induced hyperphagia and weight gain.

Materials: 

Adult female Sprague-Dawley rats received stereotaxic adenoviral delivery containing either GFP or DN AMPK, into the ARC. After recovery, rats were administered an intramuscular OLZ long-acting formulation or vehicle. Food intake and body weight were recorded daily for nine consecutive days, and hypothalamic pACC levels were measured by Western blotting after sacrifice as an indicator of AMPK activity.

Results: 

Immunoblotting demonstrated that long-acting OLZ formulation induced hyperphagia and weight gain, with similar effect in rats injected with GFP or DN AMPK adenoviral vectors. In rats injected with GFP, OLZ treatment resulted in a massive increase of pACC in the ARC, while no OLZ-induced increase was observed in rats receiving DN AMPK.

Conclusions: 

The results demonstrate that intramuscular long-acting injection of OLZ induces hyperphagia and weight gain in female rats and that this effect occurs independent of AMPK activation in ARC. Our results contrasts previous studies suggesting that hypothalamic AMPK activation is essential for the orexigenic effect of antipsychotic drugs. Further investigations concerning the role of hypothalamic lipid metabolism in antipsychotic-induced hyperphagia are warranted.