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 H3 receptor agonist (R)-alpha-methylhistamine inhibited, while superfusion with thioperamide (H3 antagonist) enhanced histamine release. Superfusion with carbachol (a mixed M1, M2, M3 agonist) inhibited the release of histamine. The release of endogenous histamine was enhanced on superfusion with atropine (a mixed M1, M2, M3 antagonist). The M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine enhanced the release rate of histamine. It is concluded that in the anterior hypothalamus the release of endogenous histamine is modulated by H3 autoreceptors. Moreover, acetylcholine released from cholinergic neurons also modulates the release of histamine via M1 and/or M3 heteroreceptors.