There is increasing evidence that neuropeptide-Y (NPY) exerts a stimulatory effect on the hypothalamo-pituitary-adrenal axis. Although it has been suggested that this stimulatory effect may be mediated via an action on hypothalamic CRF-41 release, direct measurements have not previously been made. In this study, the direct effect of NPY on hypothalamic CRF-41 secretion has been investigated in vitro using acute hypothalamic explants and previously described incubation techniques. NPY in the concentration range 10(-8)-10(-5) M produced a dose-dependent stimulation of CRF-41 release which was maximum at a concentration of 10(-6) M. The possibility that this stimulatory effect might reflect an interaction with noradrenergic inputs to CRF-41 neurons was excluded by incubating the hypothalami in the presence of NPY in combination with either the beta-adrenoceptor antagonist, propranolol (10(-5) M), or the alpha 1-adrenoceptor antagonist, prazosin (10(-5) M); neither inhibited NPY-stimulated CRF-41 release, suggesting that this effect is unrelated to noradrenergic pathways and is exerted through distinct receptor mechanisms. Furthermore, norepinephrine-stimulated (10(-8)-10(-6) M) CRF-41 release was not potentiated in the presence of NPY (10(-6) M). In summary, these data provide evidence for a direct stimulatory effect of NPY on CRF-41 secretion from the rat hypothalamus in vitro. This effect is independent of catecholaminergic interactions, suggesting that it is mediated either directly on CRF-41 neurons or through non-catecholaminergic neuronal systems.