Central injection of alpha-melanocyte-stimulating hormone (alpha-MSH) decreases food intake, suggesting a role for this peptide in the mediation of satiety. Inasmuch as alpha-MSH also supports the development of taste aversions under certain conditions, the nature of its influence on ingestive behavior, i.e., whether it is related to satiety or aversion, remains unclear. In the present studies, we used immunostaining, including that for c-Fos as a marker of neuronal activation, to further substantiate the physiological role for alpha-MSH in the regulation of consummatory behavior. We found that an increase in activation of alpha-MSH neurons in the arcuate nucleus coincided with meal termination. Administration of powerful aversive agents, LiCl and CuSO(4), did not stimulate alpha-MSH cells but did induce pronounced activation of oxytocin (OT) and vasopressin (VP) neurons, the final components of circuitry mediating aversion. We observed fewer Fos-positive OT/VP neurons after alpha-MSH injection into the lateral ventricle or into the hypothalamic paraventricular nucleus, treatments that cause mild or no aversion, respectively. The degree of activation of OT/VP neurons paralleled the magnitude of aversive response to a given treatment. Our data support the hypothesis that, in the arcuate nucleus, alpha-MSH acts as a satiety mediator independent from aversion-related mechanisms.