Corticotropin-Releasing Factor Increases GABA Synaptic Activity and Induces Inward Current in 5-Hydroxytryptamine Dorsal Raphe Neurons

• DOI: 10.1523/jneurosci.2887-08.2008
• Publication Date: 2008-11-26T18:29:23Z
• Authors: Lynn G. Kirby; Emily Freeman-Dan...; Julia C. Lemos; John D. Nunan; Christophe Lamy; Adaure Akanwa; Sheryl G. Beck
• Keywords: Male; Neurons; Serotonin; Patch-Clamp Techniques; Corticotropin-Releasing Hormone; Cell Membrane; Neural Inhibition; Receptors, Corticotropin-Releasing Hormone; Synaptic Transmission; Rats; Rats, Sprague-Dawley; 03 medical and health sciences; Organ Culture Techniques; 0302 clinical medicine; Inhibitory Postsynaptic Potentials; Mesencephalon; Synapses; Animals; Raphe Nuclei; gamma-Aminobutyric Acid

Stress-related psychiatric disorders such as anxiety and depression involve dysfunction of the serotonin [5-hydroxytryptamine (5-HT)] system. Previous studies have found that the stress neurohormone corticotropin-releasing factor (CRF) inhibits 5-HT neurons in the dorsal raphe nucleus (DRN)in vivo. The goals of the present study were to characterize the CRF receptor subtypes (CRF-R1 and -R2) and cellular mechanisms underlying CRF–5-HT interactions. Visualized whole-cell patch-clamp recording techniques in brain slices were used to measure spontaneous or evoked GABA synaptic activity in DRN neurons of rats and CRF effects on these measures. CRF-R1 and -R2-selective agonists were bath applied alone or in combination with receptor-selective antagonists. CRF increased presynaptic GABA release selectively onto 5-HT neurons, an effect mediated by the CRF-R1 receptor. CRF increased postsynaptic GABA receptor sensitivity selectively in 5-HT neurons, an effect to which both receptor subtypes contributed. CRF also had direct effects on DRN neurons, eliciting an inward current in 5-HT neurons mediated by the CRF-R2 receptor and in non-5-HT neurons mediated by the CRF-R1 receptor. These results indicate that CRF has direct membrane effects on 5-HT DRN neurons as well as indirect effects on GABAergic synaptic transmission that are mediated by distinct receptor subtypes. The inhibition of 5-HT DRN neurons by CRFin vivomay therefore be primarily an indirect effect via stimulation of inhibitory GABA synaptic transmission. These results regarding the cellular mechanisms underlying the complex interaction between CRF, 5-HT, and GABA systems could contribute to the development of novel treatments for stress-related psychiatric disorders.