To investigate the modulation of histamine release by autoreceptors and heteroreceptors, the rat anterior hypothalamus was superfused through a push-pull cannula with agonists or antagonists of histamine and acetylcholine muscarinic receptors. Superfusion with the H-3 receptor agonist (R)-alpha-methylhistamine inhibited, while superfusion with thioperamide (H-3 antagonist) enhanced histamine release. Superfusion with carbachol (a mixed M(1), M(2), M(3) agonist) inhibited the release of histamine. The release of endogenous histamine was enhanced on superfusion with atropine (a mixed M(1), M(2), M(3) antagonist). The M(3) muscarinic antagonist 4-diphenylacet-oxy-N-methylpiperidine enhanced the release rate of histamine. It is concluded that in the anterior hypothalamus the release of endogenous histamine is modulated by H-3 autoreceptors. Moreover, acetylcholine released from cholinergic neurons also modulates the release of histamine via M(1) and/or M(3) heteroreceptors.