Effects of histamine and related agonists and antagonists on formation of cAMP were determined for enzymatically dissociated ganglia from the myenteric plexus of the guinea-pig small intestine. Formation of cAMP was stimulated by histamine in both dose- and time-dependent manners. The stimulatory action of histamine was suppressed by the histamine H2 receptor antagonist, cimetidine. The histamine H1 receptor antagonists, tripelennamine or pyrilamine also suppressed the stimulatory action of histamine, but only at concentrations 3-4 orders higher than required for cimetidine. Formation of cAMP was stimulated dose-dependently by the histamine H2 receptor agonist, dimaprit. The histamine H1 receptor agonist, 2-methyl-histamine, also stimulated cAMP production, but required a threshold concentration 4-5 orders higher than dimaprit. We conclude that histamine acts at the histamine H2 receptor subtype to stimulate adenylate cyclase and the formation of cAMP in myenteric ganglia of the guinea-pig small bowel.