The effects of cholinergic agents on the K(+)-evoked release of endogenous histamine from hypothalamic slices of rats were examined by a superfusion method in vitro. Acetylcholine and carbamylcholine significantly inhibited K(+)-evoked release of histamine from the slices, and the effect of acetylcholine was antagonized by the muscarinic antagonist atropine. On the other hand, nicotine significantly enhanced the K(+)-evoked release and its effect was antagonized by the nicotinic antagonist hexamethonium. The effects of carbamylcholine and nicotine on histamine release from slices of whole hypothalamus and from slices of the anterior hypothalamic region, which do not contain cell bodies of the histaminergic neurons, were the same. Thus, the K(+)-evoked release of endogenous histamine from histaminergic fibers in the hypothalamic slices was inhibited by muscarinic agents and enhanced by nicotinic agents. These results suggest that muscarinic and nicotinic receptors exert antagonistic effects on the release of hypothalamic histamine from in vitro slice preparations. The cholinergic receptors modulating histamine release might be located presynaptically on the histaminergic terminals.