Do centrally administered neuropeptides access cognate receptors? An analysis in the central corticotropin-releasing factor system

To determine the extent to which centrally administered corticotropin-relea sing factor (CRF) activates neurons that express CRF receptors (CRF-Rs), we followed the kinetics and distribution (relative to those of CRF-Rs) of Fo s induction seen in response to intracerebroventricular (icv) injection of the peptide (1-10 mg). CRF provoked widespread Fos expression: its strength was dose-related, it peaked at 2 hr after injection, and it was antagonize d in a dose-dependent manner by coinjection of CRF-R antagonists. The activ ation pattern closely mimicked the distribution of CRF-R1 mRNA, in includin g widespread Fos induction throughout the cortical mantle, in cell groups i nvolved in sensory information processing, and in the cerebellum and severa l of its major afferents and targets. Dual labeling revealed extensive corr espondence of CRF-stimulated Fos-immunoreactivity (Fos-ir) and CRF-R1 mRNA at these and other loci. Unique sites of CRF-R2 expression were relatively unresponsive to CRF but were more so after icv administration of urocortin (UCN), a new mammalian CRF-related peptide. Both CRF and UCN elicited activ ational responses in cell groups that are involved in central autonomic con trol but that express neither CRF-R, including the central amygdaloid and p araventricular hypothalamic nuclei, and brainstem catecholaminergic cell gr oups. The results support an ability of CRF-related peptides in the ventric ular system to access receptor-expressing cells directly but leave open que stions as to the basis for the recruitment of central autonomic structures, many of which have been identified as stress-related sites of CRF action.