The effect of intracerebroventricular administration of histamine on hypothalamic dopaminergic neuronal activity was estimated in male rats by measuring concentrations of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in brain regions containing terminals or perikarya of these neurons. Three distinct, regionally specific neurochemical responses were apparent. In the median eminence and intermediate lobe of the pituitary, histamine affected neither DOPAC nor dopamine concentrations, suggesting no effect on tuberoinfundibular or periventricular-hypophysial dopaminergic neuronal activity. In the medial zona incerta and in the dorsomedial, rostral periventricular and medial preoptic hypothalamic nuclei, histamine effected a dose- and time-related increase in both DOPAC and dopamine concentrations; these effects were blocked by destruction of noradrenergic neurons projecting to these regions, suggesting that these changes are attributable to noradrenergic neuronal activation, and that histamine does not affect the activity of incertohypothalamic or periventricular-preoptic dopaminergic neurons located in these brain regions. In the suprachiasmatic, caudal periventricular and paraventricular hypothalamic nuclei, histamine effected a dose- and time-related increase in DOPAC, but not dopamine, concentrations; these effects were blocked by the H1 antagonist mepyramine, but not the H2 antagonist zolantidine. Destruction of noradrenergic neurons projecting to these regions did not prevent the histamine-induced increases in DOPAC concentrations. These data indicate that histamine increases the activity of dopaminergic neurons projecting to the suprachiasmatic, caudal periventricular and paraventricular nuclei via an action at H1 receptors. Overall, these results reveal that i.c.v. administration of histamine differentially affects the activity of the various dopaminergic neuronal systems of the rat hypothalamus.