The hypothalamus, which is rich in histaminergic neurons, is highly sensitive to aversive stimuli such as stress. Histamine H3 receptors, which regulate histamine release from the presynaptic site, are associated with stress-induced brain activity. In this study, we investigated the changes of histamine content and histamine H1 and H3 receptors in the brains of rats subjected to stress induced through food deprivation and physical activity on a running wheel (food-deprived activity stress). For purposes of comparison, we also examined the stressful effects of forced swimming on the histaminergic neuron system of rats. The H3 receptor density rapidly declined in the acute phase of stress but gradually returned to the control level in the chronic phase. On the other hand, the H1 receptor slowly decreased and remained at a low level during the chronic phase. These results reveal that there is a discrepancy between the levels of H1 and H3 receptors in the acute and chronic phases of stress. Brain histamine content gradually increased during the late phase of both food-deprived activity stress and forced swimming stress. These changes presumably resulted in the inhibition of histaminergic neuronal activity in the chronic stress condition. In accordance with this hypothesis, the intraventricular administration of histamine significantly reduced the hyperactivity caused by food-deprived activity stress. Since extensive exercise and restricted feeding are thought to be associated with anorexia nervosa, the abnormalities in the histaminergic neuron system might contribute to trait status in anorexia nervosa.