Bath application of sulfated or non-sulfated cholecystokinin octapeptide (CCK-8s or CCK-8ns, respectively) at concentrations of 25 to 250 nM stimulated the firing activity of 40 to 80% of neurons recorded from the ventromedial nucleus (VMN) in hypothalamic slices maintained in vitro. On the basis of molarity or the percentages of neurons affected, CCK-8s was about 2 to 10 times more potent than CCK-8ns. However, qualitatively, the two forms of CCK-8 were virtually identical: both had a stimulatory action on VMN neurons; both affected VMN neurons in a dose-dependent fashion; both could desensitize their own stimulatory action; and both could cross-desensitize the stimulatory action of the other. These results indicate that not only CCK-8s but also CCK-8ns, which is biologically inactive peripherally, can serve as excitatory neurotransmitters in the VMN, and that both peptides stimulated neurons through the same or a similar neuronal mechanism. It was also found that in the VMN, the stimulatory action of CCK-8 correlated with the actions of norepinephrine, and affected all of the VMN neurons responsive to glucose. Since the actions of glucose and norepinephrine on the activity of VMN neurons are feeding-relevant, our data support the notion that, in addition to acting as a peripheral satiety agent, CCK-8 can also act as a neurotransmitter centrally to mediate satiety.