High-fat intake induced by mu-opioid activation of the nucleus accumbens is inhibited by Y1R-blockade and MC3/4R- stimulation

Nucleus accumbens mu-opioid receptor activation can strongly stimulate intake of high-fat food in satiated rats, and one of the mechanisms involves activation of lateral hypothalamic orexin neurons and orexin receptor-1 signaling in the mesolimbic dopamine system. Here, we tested the potential contribution of NPY/Y1R and α-MSH/MC3/4R-signaling to accumbens-induced high-fat feeding. Prior administration of the selective Y1R antagonist 1229U91 or the MC3/4R agonist MTII into the lateral ventricle (LV) dose-dependently decreased high-fat intake induced by nucleus accumbens injection of the mu-opioid receptor agonist DAMGO. Both drugs also decreased high-fat feeding induced by switching rats from regular chow to high-fat diet, but less efficiently than when DAMGO-induced. Administration of 1229U91 directly into the PVH also suppressed DAMGO-induced high-fat intake, but a higher dose was required. The results suggest that NPY/Y1R signaling in the PVH and other forebrain sites is necessary for accumbens DAMGO to elicit high-fat intake, and that forebrain MC3/4R signaling can suppress it.