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The Journal of Neuroscience, October 15, 2000, 20(20):7728-7736

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

Christopher A. Lowry, Joanne E. Rodda, Stafford L. Lightman, and Colin D. Ingram

University of Bristol, University Research Centre for Neuroendocrinology, Bristol, BS2 8HW, United Kingdom

In vivo studies suggest that the stress-related neuropeptide corticotropin-releasing factor (CRF) modulates serotonergic neurotransmission. To investigate the underlying mechanisms for this interaction, the present study examined the effects of CRF in vitro on dorsal raphe neurons that displayed electrophysiological and pharmacological properties consistent with a serotonergic phenotype. In the presence of either 1 or 2 mM Ca²⁺, perfusion of ovine CRF or rat/human CRF rapidly and reversibly increased firing rates of a subpopulation (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 tachyphylaxis. Excitatory effects were dose-dependent (over the range of 0.1-1.6 µM) and were completely absent after exposure to the competitive CRF receptor antagonists -helical CRF_9-41 or rat/human [D-Phe¹², Nle^21,38, -Me-Leu³⁷]-CRF_12-41. 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 prepared 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 hydroxylase-immunoreactive neurons in the area of the recordings, providing anatomical evidence for potential direct actions of CRF on serotonergic neurons. The electrophysiological properties and the distribution of responsive neurons within the dorsal raphe nucleus are consistent with the hypothesis that endogenous CRF activates a topographically organized mesolimbocortical serotonergic system.

Key words: anxiety; conditioned fear; corticotropin-releasing hormone; CRF; CRH; drug addiction; drug withdrawal; serotonin; mesolimbic; mesolimbocortical; serotonergic; restraint; isolation; sensitization; stress

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20207728-09$05.00/0

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