Effects of Corticotropin-Releasing Factor on Neuronal Activity in the Serotonergic Dorsal Raphe Nucleus

Abstract

The present study examined the regional localization of corticotropin-releasing factor (CRF)-and 5-hydroxytryptamine (5-HT)-immunoreactive (IR) fibers within the rat dorsal raphe nucleus (DRN) using immunohistochemistry. Additionally, the effects of CRF, administered intracerebroventricularly (0.1-3.0 g) or intraraphe (0.3-30 ng), on discharge rates of putative 5-HT DRN neurons Corticotropin-releasing factor (CRF) has a diverse range of physiological and behavioral effects, acting both as a neurohormone at the level of the anterior pituitary and as a neurotransmitter in brain. As a neurohormone, CRF initiates the release of adrenocorticotropic hormone which triggers the endocrine limb of the stress response . Anatomical evidence of a widespread distribution of CRF-immunoreactive (IR) terminals and receptors throughout the brain De Souza et al. 1985;Potter et al. 1994;Sakanaka et al. 1987;Swanson et al. 1983) provides support for the additional role of CRF as a brain neurotransmitter. An example of a potential neurotransmitter action of CRF is its action on the locus coeruleus (LC)-norepinephrine system. Intracerebroventricular (i.c.v.) or intracoerulear administration of CRF increases activity of LC neurons Page and Abercrombie 1999;Valentino et al. 1983) and stimulates NE release in terminal fields of the LC (Lavicky and Dunn 1993;Page and Abercrombie 1999;Smagin et al. 1995). Moreover, activation of LC neurons by certain physiological stimuli is attenuated by CRF antagonists administered into the LC (Curtis et al. 1994;Lechner et al. 1997).Anatomical evidence suggests that CRF is also positioned to affect activity of the dorsal raphe nucleus Philadelphia, PA 19102. Received May 17, 1999; revised July 28, 1999; accepted August 3, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 2 CRF Effects on 5-HT Neurons 149 (DRN)-5-hydroxytryptamine (5-HT) system. Thus, CRF receptor binding sites (De Souza et al. 1985) and mRNA Potter et al. 1994) as well as CRF-IR terminals (Sakanaka et al. 1987;Swanson et al. 1983) are localized in the DRN, a primary site of 5-HT cell bodies projecting to the forebrain. Recent studies demonstrated that relatively low doses of CRF (administered i.c.v.) inhibit 5-HT release in two different terminal regions of the DRN (i.e., striatum and lateral septum), suggesting that the site of action of CRF effects on 5-HT release is at the level of the cell bodies in the DRN . Consistent with this, electrophysiological recordings indicated that a low dose of CRF (administered i.c.v.) that decreased extracellular levels of 5-HT in striatum also decreased DRN discharge rate . In contrast to the effects of low doses of CRF, higher doses were found to not alter or to increase extracellular 5-HT levels in the lateral septum or striatum, respectively. The complex dose-related effects of CRF on 5-HT release could be a function of multiple CRF receptor subtypes within the DRN and/or different sites of action (cell bodies vs. terminals) of i.c.v. administered CRF.The present study was designed t...

The role of prior stressor controllability and the dorsal raphé nucleus in sucrose preference and social exploration

“…In the DRN the serotonin 1A receptor (5-HT1A) behaves as an inhibitory somato-dendritic autoreceptor. 8-OH-DPAT is a 5-HT1A agonist and can be used to silence serotonergic neuronal activity [19]. Since ES does not alter social exploration (Experiment 1 and [44]) or sensitize the DRN [2], there would be no effect of ES to block.…”

“…20 min prior to IS, stressed and HC rats received a microinjection of 8-OH-DPAT or saline. This method has been used frequently to inhibt DRN 5-HT activity [19,24,47]. After stress rats were tested for sucrose preference and social exploration as in Experiment 2.…”

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

“…CRF-evoked grooming was also attenuated by propranolol but this could not distinguish between a role for NE and 5-HT due to the nonselective effects of this antagonist. Studies of intraventricular and intra-raphe CRF administration provide substantial evidence for CRF-mediated modulation of serotonergic transmission (de Groote et al 2005;Kirby et al 2000;Price et al 1998;Price and Lucki 2001). The anxiogenic effects of CRF, including increased grooming behavior, have been linked with its activation of serotonergic transmission (Kagamiishi et al 2003;Lazosky and Britton 1991).…”

“…CRF administration, i.c.v. and site-specifically, alters the firing of NE and 5-HT neurons (Kirby et al 2000;Price et al 1998;Valentino and Foote 1987), and modulates neurotransmitter release at their respective terminal fields de Groote et al 2005;Price and Lucki 2001). Evocation of anxiety responses by CRF infusion is accompanied by concomitant changes in forebrain 5-HT (Kagamiishi et al 2003) and NE transmission.…”

Chronic low dose ovine corticotropin releasing factor or urocortin II into the rostral dorsal raphe alters exploratory behavior and serotonergic gene expression in specific subregions of the dorsal raphe

“…Indeed, neurons in different subregions of the DRN respond to CRF in a divergent manner depending on the subregion and location along the anteroposterior axis (Amat et al, 1998, Price et al, 1998, Kirby et al, 2000, Lowry et al, 2000, Hammack et al, 2002, Price et al, 2002, Pernar et al, 2004. However, with the exception of post-traumatic stress disorder, single acute stressor exposure rarely induces the development of psychiatric illness.…”