Effects of Corticotropin-Releasing Factor on Brain Serotonergic Activity

Abstract

The serotonergic dorsal raphe nucleus is innervated by corticotropin-releasing factor (CRF) and expresses CRF receptors, suggesting that endogenous CRF impacts on this system. The present study characterized interactions between CRF and the dorsal raphe serotonin (5-HT) system. The effects of intracerebroventricularly (i.c.v.) administered CRF on microdialysate concentrations of 5-HT in the lateralCorticotropin-releasing factor (CRF) is the hypothalamic neurohormone that initiates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary during stress (Vale et al. 1981). In addition, CRF is thought to function as a brain neurotransmitter that interacts with other neurotransmitter systems to coordinate autonomic and behavioral components of the stress response (Dunn and Berridge 1990;Owens and Nemeroff 1991;Valentino et al. 1993). This is supported by anatomical studies that have identified a widespread distribution of CRF-immunoreactive neurons and fibers outside of the hypothalamic-pituitary axis in brain regions that are not directly involved with endocrine responses to stress (Sakanaka et al. 1987;Swanson et al. 1983). This distribution far exceeds that required for CRF-evoked release of ACTH. Consistent with this widespread distribution of CRF-immunoreactive terminals, CRF receptor binding sites and CRF receptor mRNA are localized in diverse brain regions that are unrelated to their pituitary actions (Chalmers et al. 1995;De Souza 1987;Potter et al. 1994).Among the brain regions that are both innervated by CRF-immunoreactive fibers (Sakanaka et al. 1987;Swanson et al. 1983) and that contain mRNA for CRF receptors (Chalmers et al. 1995;Potter et al. 1994) are the dorsal and median raphe nuclei, the source nuclei of forebrain serotonergic innervation (Azmitia and Segal 1978;Kellar et al. 1977;Vertes 1991 dence for an impact of stress on forebrain 5-HT (Chaouloff 1993;De Souza and Van Loon 1986;Dunn 1988;Morgan et al. 1975;Pol et al. 1992;Tanaka et al. 1983), these anatomical findings lead to the speculation that CRF release within the raphe nucleus may mediate the effects of stress on this system. Nonetheless, there are few reports of the effects of CRF on measures of 5-HT function, and these have yielded equivocal results. For example, relatively high doses of CRF failed to alter levels of the 5-HT precursor, 5-hydroxytryptophan (Van Loon et al. 1982). Similarly, tissue levels of 5-HT or its catabolite 5-hydroxyindoleacetic acid (5-HIAA) were unaltered by CRF (Dunn and Berridge 1987). In contrast, CRF increased activity of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of 5-HT, in cortex and midbrain (Singh et al. 1991), and 5-HIAA levels, measured by microdialysis, in hypothalamus and prefrontal cortex (Lavicky and Dunn 1993). Each of these studies used relatively indirect measures of 5-HT activity. A recent study, using in vivo microdialysis to measure extracellular 5-HT levels in the hippocampus of freely-moving rats, found no change after long term administration of ...

Brainstem neuronal and behavioral activation by corticotropin-releasing hormone depend on the behavioral state of the animal

“…The present results also augment previous findings indicating a rostral brainstem involvement in CRH-stimulated locomotion (Lowry et al, 2009, 2000; Price et al, 1998; Tazi et al, 1987; Valentino et al, 1993; Waselus et al, 2011), where ascending projections from the rostral brainstem would modulate forebrain processes such as cognitive and emotional effects of CRH, whereas the peptide’s action on hindbrain neurons, many of which internalize CRH (Lowry and Moore, 2006; Hubbard, et al, 2010), would more directly regulate locomotion.…”

“…Stimulation of locomotion by CRH has been particularly studied as a robust model for this peptide’s behavioral effect. Prior research has focused on CRH’s upstream actions; on ascending serotonergic and noradrenergic neuromodulatory systems arising from midbrain and rostral pontine nuclei, such as the dorsal raphé nucleus, locus coeruleus, and their respective targets in the ventral forebrain (Lowry et al, 2009, 2000; Price et al, 1998; Tazi et al, 1987; Valentino et al, 1993). On the other hand, potential CRH actions on the medullary reticular formation (MRF), a region containing reticulospinal (RS) neurons critically involved in initiation and regulation of vertebrate rhythmic locomotion has been less investigated (Lowry and Moore, 2006; Lowry et al, 1996).…”

Localisation and stress-induced plasticity of GABAA receptor subunits within the cellular networks of the mouse dorsal raphe nucleus

“…The bath application of CRH to acute brain slices containing the DRN decreases serotonergic neuronal activity by enhancing both the local release of GABA as well as the postsynaptic GABA receptor sensitivity (Kirby et al 2008). Furthermore, the intracerebroventricular administration of CRH directly influences DRN neuronal excitability and serotonin release in DRN target fields (Price et al 1998;Price and Lucki 2001;Kirby et al 2000). We therefore investigated a possible anatomical basis for an interaction between mouse DRN GABA A R and CRH systems by examining the association of the GABA A R molecular machinery, with that of CRH on the cell types of the DRN.…”

Fibromyalgia: A Stress Disorder?

“…These data may be explained by increased receptor binding of CRH in the nucleus raphe [56], leading to decreased activity of serotonergic neurons [57]and lack of inhibition of nociceptive stimuli by descending pain-controlling mechanisms [58]. Moreover, due to limbic connections between stress-regulating and pain-processing mechanisms, memories of childhood pain may in later life be triggered by physical as well as psychological stressors, without the presence of a specific nociceptive stimulus [59, 60, 61].…”