Manipulating neuronal histamine in the hypothalamus, its effects on brain functions were assessed in nonobese normal rats and Zucker rats. Alpha-fluoromethylhistidine (FMH), an inhibitor of histamine synthesis, induced feeding dose-dependently after 2.24 mumol infusion at 1100 h, when hypothalamic histamine was normally high. This dose of FMH selectively decreased hypothalamic histamine, but not other neurotransmitters. Thioperamide, an antagonist of autoinhibitory H3-receptors, decreased food intake after infusion at 1940 h, when hypothalamic histamine was normally low. Bilateral microinfusion of 224 nmol FMH or 26 nmol chlorpheniramine, an H1-antagonist, into the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN), elicited feeding. However, Zucker obese rats showed no significant responses to chlorpheniramine, thioperamide or histamine. Concentration of their hypothalamic histamine was excessively lower than that of the nonobese. Contents of hypothalamic histamine were lowered at 4 degrees C and raised at 31 degrees C. FMH attenuated increase in histamine, and then disrupted adaptive behavior. These findings indicate that neuronal histamine may convey the suppressive signal of food intake through H1-receptors in the VMH and/or the PVN, and play critical roles in homeostatic control of adaptive behavior.