The involvement of central histaminergic mechanisms in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by carbachol, a muscarinic cholinergic agonist, was investigated in conscious rats. The HPA activity was assessed indirectly, through corticosterone secretion. Carbachol given intracerebroventricularly elicited a dose-related increase in serum corticosterone levels. The corticosterone response to carbachol was totally abolished by systemic pretreatment 2h earlier with alpha-fluoro-methylhistidine (alpha-FMH), a specific inhibitor of brain histamine synthesis, which also significantly decreased histamine level in hypothalamus. Mepyramine, a histamine H1-receptor antagonist, moderately diminished the carbachol-induced corticosterone response and abolished the rise in hypothalamic histamine levels. Ranitidine a H2-receptor antagonist, considerably diminished the corticosterone response to carbachol but did not change the elevated hypothalamic histamine levels. Also atropine, a cholinergic antagonist, abolished the corticosterone response to carbachol, but did not significantly affect the carbachol-induced increase in hypothalamic histamine concentration. Ranitidine and atropine can directly block homologous hypothalamic receptors involved in CRF secretion. Partial inhibition of the carbachol-induced corticosterone secretion by mepyramine may be connected with prevention of the carbachol-induced increase in hypothalamic histamine content. These results suggest that hypothalamic histamine and histamine receptors are involved in the HPA stimulation by the muscarinic agonist carbachol.