Selective Activation of Corticotropin-Releasing Factor-2 Receptors on Neurochemically Identified Neurons in the Rat Dorsal Raphe Nucleus Reveals Dual Actions

Pernar, Luise I.M.; Curtis, Andre L.; Vale, Wylie; Rivier, Jean; Valentino, Rita J.

doi:10.1523/jneurosci.2885-03.2004

Cited by 118 publications

(117 citation statements)

References 34 publications

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“…Activation of CRF 2 receptors in the dRN appear to increase firing rates of 5-HT neurons, probably by disinhibition of 5-HT neuronal activity by CRF 2 -mediated inhibition of non-serotonergic (presumably GABAergic) neurons within the dRN [35]. Likewise, CRF 2 receptors in the dRN are required for CRFinduced release of 5-HT within another forebrain limbic site, the nucleus accumbens, whereas CRF type 1 receptor activation results in decreased accumbal 5-HT release [28].…”

Section: Discussionmentioning

confidence: 99%

Restraint stress increases serotonin release in the central nucleus of the amygdala via activation of corticotropin-releasing factor receptors

Mo¹,

Feng²,

Renner³

et al. 2008

Brain Research Bulletin

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Decreases in serotonergic activity in the central nucleus of the amygdala reduce responses to stressors, suggesting an important role for serotonin in this region of the amygdala in stress reactivity. However, it is not known whether exposure to stressors actually increases serotonin release in the central nucleus of the amygdala. The current experiment tested the hypothesis that restraint stress increases extracellular serotonin within the central nucleus of the amygdala and adjacent medial amygdala using in vivo microdialysis in awake male rats during the dark phase of the light-dark cycle. Serotonin release in the central nucleus increased immediately in response to restraint stress. In contrast, there was no change in serotonin release within the adjacent medial amygdala during or following restraint. Since corticotropin-releasing factor is an important mediator of both responses to stressors and serotonergic activity, subsequent experiments tested the hypothesis that central nucleus serotonergic response to restraint stress is mediated by central corticotropin-releasing factor receptors. Administration of the corticotropin-releasing factor type 1 and 2 receptor antagonist DPhe-CRF (icv, 10 μg/5 μl) prior to restraint stress suppressed restraint-induced serotonin release in the central nucleus. The results suggest that restraint stress rapidly and selectively increases serotonin release in the central nucleus of the amygdala by the activation of central corticotropin-releasing factor receptors. Furthermore, the results imply that corticotropin-releasing factor mediated serotonergic activity in central nucleus of the amygdala may be an important component of a stress response.

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Section: Discussionmentioning

confidence: 99%

Restraint stress increases serotonin release in the central nucleus of the amygdala via activation of corticotropin-releasing factor receptors

Mo¹,

Feng²,

Renner³

et al. 2008

Brain Research Bulletin

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“…Because a single dose of 1ng was found to be the smallest intraraphe dose of oCRF and UCNII effective in altering DRN discharge (Kirby et al, 2000, Pernar et al, 2004 an infusion rate of 1ng/hr was selected for both peptides in order to produce chronic low levels of DRN activation or inhibition.…”

Section: Mean Cannula Placement and Peptide Stabilitymentioning

confidence: 99%

“…Of particular note, CRF receptor distribution in DRN is complex and varies by region (Day et al, 2004, Pernar et al, 2004. Recent reports have emphasized the discrete subregional nature of DRN response to both direct and indirect (via the basolateral amygala) exposure to CRF receptor ligands (Forster et al, 2006, Spiga et al, 2006.…”

Section: Serotonergic Gene Expression Following Chronic Crf Receptor mentioning

confidence: 99%

“…These peptides may respond differently under acute and chronic stress exposure than the serotonergic component. The internal anatomical complexity of the DRN has been more clearly appreciated recently (Rattray et al, 1999, Commons et al, 2003, Abrams et al, 2004, Abrams et al, 2005, Greenwood et al, 2005, Clark et al, 2006, and discrete changes in serotonergic gene expression in subregions of raphe could be sufficient to induce substantial behavioral changes.Of particular note, CRF receptor distribution in DRN is complex and varies by region (Day et al, 2004, Pernar et al, 2004. Recent reports have emphasized the discrete subregional nature of DRN response to both direct and indirect (via the basolateral amygala) exposure to CRF receptor ligands (Forster et al, 2006, Spiga et al, 2006.…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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

et al. 2007

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Corticotropin releasing factor (CRF) family peptides play key roles in integrating neural responses to stress. Both major CRF receptors have been pharmacologically identified in the dorsal raphe nucleus (DRN), a stress sensitive and internally heterogeneous nucleus supplying many forebrain regions with serotonergic input. Despite the involvement of chronic stress and serotonergic dysfunction in human mood and anxiety disorders, little is known about the effects of chronic CRF receptor activation on the DRN. We infused ovine CRF (1ng/hr), urocortin II (UCNII, 1ng/hr), or vehicle alone into rat DRN over 6 days. During infusion, animals were allowed to freely explore an open field for 15 minutes on each of two days, with the addition of a novel object on the second day. Following behavioral testing, 5-HT 1A , 5-HT 1B , serotonin transporter (SERT), and tryptophan hydroxylase-2 (Tph2) expression were examined through the DRN by in situ hybridization. Ovine CRF infusion resulted in significantly decreased novel object touches, climbs, as well as increased latency to first novel object contact. UCNII had a similar but less dramatic effect, decreasing only climbing behavior. Both ovine CRF and UCNII blunted the decrease in corner time expected on reexposure to the open field. Both peptides also produced regionally specific changes in gene expression: 5-HT 1A expression was increased 30% in the mid-rostral ventromedial DRN, while SERT was decreased by 30% in the mid-caudal shell dorsomedial DRN. There also appeared to be a shift in the relative level of Tph2 expression between the ventromedial and core dorsomedial DRN at the mid-rostral level. Changes in 5-HT 1A , SERT, and relative Tph2 mRNA abundance were correlated with novel object exploration. These findings suggest chronic intra-DRN administration of CRF agonists decreases exploratory behavior, while producing subregionally limited changes in serotonergic gene expression. These studies may be relevant to mechanisms underlying behavioral changes after chronic stress. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptDepression and anxiety disorders are among the leading causes of morbidity, mortality, and disability in the United States (Greenberg et al., 2003). They are often comorbid, and both are highly associated with chronic exposure to stress. Multiple lines of evidence suggest that chronic and inescapable stress produce long lasting effects on brain function and behavior that play a prominent role in the development, maintenance, and recurrence of both depression and a variety of anxiety disorders (Gulley and Nemeroff, 1993, Arborelius et al., 1999, Ressler and Nemeroff, 2000.Altered serotonin neurotransmission appears to be a central mechanism inducing both depressive (Maes and Meltzer, 1995) and anxiety disorders (Ressler and Nemeroff, 2000). The majority of serotonergic fibers to forebrain regions thought to be involved in mood and anxiety regulation arise from the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN) ...

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Ultrastructural evidence for a role of γ‐aminobutyric acid in mediating the effects of corticotropin‐releasing factor on the rat dorsal raphe serotonin system

Waselus

Valentino

Bockstaele

2004

J of Comparative Neurology

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The dorsal raphe nucleus (DRN) serotonin (5-HT) system has been implicated in acute responses to stress and in stress-related psychiatric disorders such as anxiety and depression. Substantial findings suggest that the neuropeptide corticotropin-releasing factor (CRF) is instrumental in modulating the activity of this system during stress. Because the DRN is neurochemically heterogeneous, dual immunoelectron microscopy was used to examine cellular substrates for interactions between CRF and either 5-HT or gamma-aminobutyric acid (GABA) in the dorsolateral and ventromedial DRN. CRF immunoreactivity was identified primarily within axon terminals, where immunolabeling was particularly enriched in dense-core vesicles. Although CRF terminals targeted 5-HT-containing dendrites in the dorsolateral DRN (16%; n = 251 terminals), synaptic contacts with dendrites that lacked detectable 5-HT immunolabeling were more numerous (48%). In contrast, dual labeling for CRF and GABA (n = 240 terminals) in the dorsolateral DRN revealed that substantially more CRF terminals contacted GABA dendrites (42%) as opposed to unlabeled dendrites (29%). In the ventromedial DRN, contacts between CRF axon terminals and either 5-HT-labeled dendrites or GABA-containing dendrites were fewer than in the dorsolateral DRN. As in the dorsolateral DRN, CRF terminals more frequently contacted GABA dendrites than 5-HT dendrites (30% vs. 8%, respectively). The findings support physiological studies suggesting that CRF has both direct and indirect effects on DRN-5-HT neurons and further implicate GABA as a primary mediator by which CRF and stressors alter the activity of the DRN-5-HT system.

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Selective Activation of Corticotropin-Releasing Factor-2 Receptors on Neurochemically Identified Neurons in the Rat Dorsal Raphe Nucleus Reveals Dual Actions

Cited by 118 publications

References 34 publications

Restraint stress increases serotonin release in the central nucleus of the amygdala via activation of corticotropin-releasing factor receptors

Restraint stress increases serotonin release in the central nucleus of the amygdala via activation of corticotropin-releasing factor receptors

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

Ultrastructural evidence for a role of γ‐aminobutyric acid in mediating the effects of corticotropin‐releasing factor on the rat dorsal raphe serotonin system

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