Recently, data have been presented showing that muscarinic cholinergic agonists or antagonists can modulate, in opposite ways, GH-releasing hormone GHRH)-induced GH release in man. The aim of the present study was, first, to confirm these findings in the rat and, secondly, if confirmed, to investigate the mechanism(s) subserving the effect of cholinergic drugs. In adult male rats bearing chronic indwelling atrial cannulae, pretreatment with the cholinergic antagonists pirenzepine (0.5 mg/kg, i.v.) or atropine (0.5 mg/kg, i.v.) significantly reduced the rise in plasma GH induced by GHRH (2 micrograms/kg, i.v.), while pretreatment with the cholinergic agonist pilocarpine (3 mg/kg, i.v.) potentiated it. In rats with hypothalamic somatostatin (SRIF) depletion, i.e. rats with anterolateral deafferentation of the mediobasal hypothalamus or rats treated with cysteamine, the modulatory action of cholinergic drugs on the neuroendocrine effect of GHRH was completely lacking. In these two experimental models, an antiserum raised against SRIF failed to elicit a rise in plasma GH and measurement of hypothalamic SRIF content revealed a clear-cut reduction of the neuropeptide. Atropine (1 mumol/l) and pilocarpine (1 mumol/l), added to pituitary cells in vitro, failed to alter GHRH-induced GH release. The present results indicate that muscarinic cholinergic agonists and antagonists modulate GHRH-induced GH release in the rat and suggest that the effect of cholinergic modulation takes place through SRIF.