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Biol Psychiatry. 2012 Jun 13;
Authors: Neufeld-Cohen A, Kelly PA, Paul ED, Carter RN, Skinner E, Olverman HJ, Vaughan JM, Issler O, Kuperman Y, Lowry CA, Vale WW, Seckl JR, Chen A, Jamieson PM
Abstract
BACKGROUND: The corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown.
CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation.
METHODS: Transgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions.
RESULTS: Mice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice.
Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response.
5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei.
CONCLUSIONS: Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders.
PMID: 22704666
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Corticotropin-Releasing Factor (CRF) is a group of peptide signals in vertebrates which includes Corticotropin-Releasing Hormone (CRH), Urocortin, Urotensin, and Sauvagine.
Corticotropin-Releasing Hormone is both a hormone and neurotransmitter. Stress stimulates the release of CRH. CRH signaling increases stress/anxiety.
CRH stimulates CRF Type 1 Receptors in the anterior pituitary gland. This then stimulates the production of Pro-Opiomelanocortin (POMC). POMC is then cleaved into numerous possible peptide signals including: Adrenocorticotropic Hormone (ACTH), Melanocyte Stimulating Hormone (Alpha, Beta, and Gamma variants), Beta-Lipotropin, Beta Endorphin, and Met-Enkephalin.
CRH stimulates CRF Type 2 Receptors in the Raphe Nuclei. The Dorsal Raphe Nucleus are the largest producer of serotonin in the central nervous system. CRH stimulation reduces the response to Serotonin (which usually reduces the severity of perceived stress, and reduces norepinephrine signaling unless there are negative interactions with other signals and metabolic factors).
I wouldn’t recommend blocking CRF Type 2 receptors with an antagonist since there will also be some blockade of Type 1 receptors. Type-1 receptor blockade impairs one’s ability to reduce stress and inflammatory signaling.