Corticotropin-releasing factor increases in vitro firing rates of serotonergic neurons in the rat dorsal raphe nucleus: Evidence for activation of a topographically organized mesolimbocortical serotonergic system

In vivo studies suggest that the stress-related neuropeptide corticotropin- releasing factor (CRF) modulates serotonergic neurotransmission. To investi gate the underlying mechanisms for this interaction, the present study exam ined the effects of CRF in vitro on dorsal raphe neurons that displayed ele ctrophysiological and pharmacological properties consistent with a serotone rgic phenotype. In the presence of either 1 or 2 mM Ca2+, perfusion of ovin e CRF or rat/human CRF rapidly and reversibly increased firing rates of a s ubpopulation (19 of 70, 27%) of serotonergic neurons predominantly located in the ventral portion of the dorsal raphe nucleus. For a given responsive neuron, the excitatory effects of CRF were reproducible, and there was no t achyphylaxis. Excitatory effects were dose-dependent (over the range of 0.1 -1.6 mu M) and were completely absent after exposure to the competitive CRF receptor antagonists alpha-helical CRF9-41 or rat/human [D-Phe(12), Nle(21 ,38), alpha-Me-Leu(37)]-CRF12-41. Both the proportion of responsive neurons and the magnitude of excitatory responses to CRF in the ventral portion of the caudal dorsal raphe nucleus were markedly potentiated in slices prepar ed from animals previously exposed to isolation and daily restraint stress for 5 d. Immunohistochemical staining of the recorded slices revealed close associations between CRF-immunoreactive varicose axons and tryptophan hydr oxylase-immunoreactive neurons in the area of the recordings, providing ana tomical evidence for potential direct actions of CRF on serotonergic neuron s. The electrophysiological properties and the distribution of responsive n eurons within the dorsal raphe nucleus are consistent with the hypothesis t hat endogenous CRF activates a topographically organized mesolimbocortical serotonergic system.