The Role of Corticotropin-Releasing Hormone in the Dorsal Raphe Nucleus in Mediating the Behavioral Consequences of Uncontrollable Stress

Abstract

Inescapable shock (IS) produces subsequent interference with escape behavior and increased fear conditioning that has been linked to increased activity and release of serotonin (5-HT) from neurons within the caudal dorsal raphe nucleus (DRN) both at the time of IS and later behavioral testing. Extrahypothalamic corticotropin-releasing hormone (CRH) has been implicated in many stress-related phenomena and has recently been shown to increase DRN 5-HT activity in the same caudal DRN area at which IS increases 5-HT activity. The current set of studies therefore examined the role of CRH in mediating the behavioral sequelae of IS. Intra-DRN microinjection of the nonselective CRH receptor antagonist D-Phe CRH (12-41) blocked the ISinduced behavioral changes when administered before IS but not when administered before later behavioral testing. Furthermore, intra-DRN administration of CRH in the absence of IS dose-dependently mimicked the effects of IS and interfered with escape behavior and increased fear conditioning 24 hr later. This effect was specific to injection of CRH into the caudal DRN and was not produced by microinjection into the rostral DRN. Intracerebroventricular CRH produced escape deficits and potentiated fear conditioning 24 hr later at only much higher doses, further confirming the site specificity of the effects. The potential role of the caudal DRN in states of anxiety is discussed.Key words: corticotropin-releasing hormone; dorsal raphe nucleus; learned helplessness; serotonin; rats; shock Corticotropin-releasing hormone (CRH) plays a key role in integrating neural, endocrine, and behavioral responses to stressful stimuli (Dunn and Berridge, 1990;Owens and Nemeroff, 1993). Although endocrine consequences of stressors are mediated by CRH-secreting cells in the hypothalamus, behavioral and neurochemical sequelae of stressor exposure are regulated by extrahypothalamic CRH (Liang et al., 1992;Lee and Davis, 1997).Serotonin (5-HT) systems are also involved in mediating reactions to stressors, and CRH has been shown to interact with 5-HT systems (Kirby et al., 2000;Lowry et al., 2000). There are CRHimmunoreactive fibers associated with 5-HT neurons in the raphe nuclei (Cummings et al., 1983;Austin et al., 1997), as well as CRH receptor mRNA expression, immunoreactivity, and binding (Cummings et al., 1983;DeSouza, 1985;Chen et al., 2000). Although the effects of CRH on 5-HT neuronal firing have been reported to be primarily inhibitory in the rostral dorsal raphe nucleus (DRN; Kirby et al., 2000), Lowry et al. (2000) have recently identified a population of 5-HT neurons in the caudal DRN that are potently excited by CRH.Interestingly, the caudal region of the DRN has been implicated in the behavioral consequences of exposure to uncontrollable stressors that have been called "behavioral depression" (Weiss et al., 1981) or "learned helplessness" (Maier and Seligman, 1976). These terms refer to the general finding that stressors over which an organism has no behavioral control produce changes that do not occu...

Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

“…24 Some overall conclusions that can be drawn from the present neurochemistry data set are that tissue concentrations of 5-HT and 5-HIAA are generally elevated in Ucn1/Ucn2 dKO mice within an anxiety-related neural circuit that receives projections from the caudal and dorsal parts of the DRN, regions of the DRN that are targeted by anxiety-related stimuli, anxiogenic drugs and anxiety-related neuropeptides, such as Ucn1 and Ucn2. 20,22,48,67,82,90,95,96 These effects are largely driven by effects of genotype on both 5-HT and 5-HIAA tissue concentrations within females, with a smaller effect of genotype in males. Analyses of additional 5-HT projection regions will reveal how widespread the effect of genotype is on increased tissue concentrations of 5-HT and 5-HIAA.…”

Intermale aggression in corticotropin-releasing factor receptor 1 deficient mice

“…Within the CNS and elsewhere, CRF acts primarily on CRFR1 [4,35,41], but can activate with less efficacy CRF receptor 2 (CRFR2) [22,39]. CRF related peptides, urocortin (Ucn) 1 and Ucn 3, can also elicit different aspects of fear and anxiety (behavioral manifestations of stress) by acting within specific brain regions [3,18,23]. Ucn 1 and Ucn 3 may be the primary ligands for CRFR2, but Ucn 1 can also activate with lesser efficacy CRFR1 [24,25,31,39].…”

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.…”