In a recent case report involving a male with hypothalamic obesity, concurrent administration of oxytocin (OT) and an opioid receptor antagonist, naltrexone (NTX), synergistically affected energy balance. Here, by using laboratory rats, we examined whether the reported synergy between OT and NTX in the context of food intake extends beyond that one unique case. We found that intravenous OT+NTX combination, at doses subthreshold for each of the drugs individually, decreased episodic consumption of a 10% sucrose solution in non-deprived animals. Daily administration of OT and NTX just before a scheduled, 2-hour, high-fat high-sugar (HFHS) meal over 24 days, decreased cumulative HFHS diet intake, but without a change in body weight due to compensatory standard chow intake during the remainder of the day. The NTX-OT treatment affected expression of several feeding-related genes in the hypothalamus, brain stem and nucleus accumbens, brain regions essential for the regulation of energy- and reward-driven consumption....

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