α-helical CRF 9-41

The effect of CRF and alpha-helical CRF((9-41)) on rat fear responses and amino acids release in the central nucleus of the amygdala.[Pubmed:19477189]

Neuropharmacology. 2009 Aug;57(2):148-56.

The effects of intracerebroventricular injections of CRF and a non-selective CRF receptor antagonist, alpha-helical CRF((9-41)), on the release of glutamate, aspartate, and GABA in the central nucleus of the amygdala (CeA), were examined in the course of testing rat anxiety-like behaviour in the conditioned fear test (a freezing response), using the microdialysis technique. It was found that CRF (1 microg/rat), given to animals exposed to the stress of novelty only, insignificantly increased the glutamate concentration in the CeA, up to 200% of the control level. In the fear-conditioned animals, the influence of CRF on the local concentration of aspartate, glutamate, and Glu/GABA ratio was much more pronounced (up to a 400% increase above the baseline level of aspartate concentration), preceded an increased expression of anxiety-like responses, and appeared as early as 15 min after the drug administration. The intracerebroventricular administration of alpha-helical CRF((9-41)) (10 microg/rat) significantly decreased the rat freezing responses and increased the local concentration of GABA during the first 30 min of observation. In sum, these are new findings, which show an important role of CRF in the CeA in the regulation of fear-controlled amino acids release and suggest an involvement of amino acids in the central nucleus of the amygdala in the effects of this neurohormone on the expression of conditioned fear.

Corticotropin releasing factor antagonist, alpha-helical CRF(9-41), reverses nicotine-induced conditioned, but not unconditioned, anxiety.[Pubmed:12669178]

Psychopharmacology (Berl). 2003 May;167(3):251-6.

RATIONALE: Unconditioned anxiogenic effects of nicotine have been observed in the social interaction (SI) test 5 min after injection of a low dose and both 5 min and 30 min after injection of a high dose. Conditioned anxiety has also been observed 24 h after testing in the SI with a high dose of nicotine. OBJECTIVES: In order to determine whether these three anxiogenic effects shared a common mechanism, we investigated the role of corticotropin releasing factor (CRF). We therefore examined whether the CRF antagonist alpha-helical CRF(9-41) could block these three anxiogenic effects of nicotine. METHODS: To test the unconditioned anxiogenic effects, pairs of male rats were tested in SI 5 min after s.c. vehicle or nicotine (0.1 mg/kg) or 30 min after s.c. vehicle or nicotine (0.45 mg/kg), and 30 min after i.c.v. artificial cerebrospinal fluid (aCSF) or alpha-helical CRF(9-41). To test conditioned anxiety, rats were exposed to the SI test on day 1, 5 min after vehicle or nicotine (0.1 mg/kg). On day 2, they were re-tested in SI 30 min after i.c.v. aCSF or alpha-helical CRF(9-41) (5 microg). RESULTS: alpha-Helical CRF(9-41) did not block the unconditioned anxiogenic effect of either dose of nicotine. Nicotine (0.1 mg/kg, 5 min) elicited a conditioned anxiogenic response that was significantly reversed by alpha-helical CRF(9-41). The CRF antagonist alone had no effect. CONCLUSIONS: CRF is an important mediator of the conditioned anxiety to nicotine, but may not play a role in mediating the acute anxiogenic effects.

Peripheral alpha-helical CRF (9-41) does not reverse stress-induced mast cell dependent visceral hypersensitivity in maternally separated rats.[Pubmed:22129370]

Neurogastroenterol Motil. 2012 Mar;24(3):274-82, e111.

BACKGROUND: Acute stress-induced hypersensitivity to colorectal distention was shown to depend on corticotropin releasing factor (CRF)-induced mast cell degranulation. At present it remains unclear whether CRF also induces chronic poststress activation of these cells. Accordingly, the objective of this study was to compare pre- and poststress CRF-receptor antagonist treatment protocols for their ability to, respectively, prevent and reverse mast cell dependent visceral hypersensitivity in a rat model of neonatal maternal separation. METHODS: The visceromotor response to colonic distention was assessed in adult maternally separated and non-handled rats before and at different time points after 1 h of water avoidance (WA). Rats were treated with the mast cell stabilizer doxantrazole and the CRF receptor-antagonist alpha-helical-CRF (9-41). Western blotting was used to assess mucosal protein levels of the mast cell protease RMCP-2 and the tight junction protein occludin. KEY RESULTS: In maternally separated, but not in non-handled rats, WA induced chronic hypersensitivity (up to 30 days) to colorectal distention. Visceral hypersensitivity was prevented, but could not be reversed by administration of alpha-helical-CRF (9-41). In contrast, however, the mast cell stabilizer doxantrazole reversed visceral hypersensitivity. Compared with vehicle-treated rats, pre-WA alpha-helical-CRF (9-41) treated animals displayed higher mucosal RMCP-2 and occludin levels. CONCLUSIONS & INFERENCES: Water avoidance-stress leads to persistent mast cell dependent visceral hypersensitivity in maternally separated rats, which can be prevented, but not reversed by blockade of peripheral CRF-receptors. We conclude that persistent poststress mast cell activation and subsequent visceral hypersensitivity are not targeted by CRF-receptor antagonists.

The influence of CRF and alpha-helical CRF(9-41) on rat fear responses, c-Fos and CRF expression, and concentration of amino acids in brain structures.[Pubmed:18601929]

Horm Behav. 2008 Nov;54(5):602-12.

In the present study we have examined the influence of intracerebroventricullary administered CRF, and a non-selective CRF receptor antagonist, alpha-helical CRF((9-41)), on rat conditioned fear response, serum corticosterone, c-Fos and CRF expression, and concentration of amino acids (in vitro), in several brain structures. Pretreatment of rats with CRF in a dose of 1 microg/rat, enhanced rat-freezing response, and further increased conditioned fear-elevated concentration of serum corticosterone. Moreover, exogenous CRF increased aversive context-induced expression of c-Fos in the parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN), CA1 area of the hippocampus, and M1 area of the frontal cortex. A different pattern of behavioral and biochemical changes was present after pre-test administration of alpha-helical CRF((9-41)) (10 microg/rat): a decrease in rat fear response and serum corticosterone concentration; an attenuation of fear-induced c-Fos expression in the dentate gyrus, CA1, Cg1, Cg2, and M1 areas of the frontal cortex; a complete reversal of the rise in the number of CRF immunoreactive complexes in the M2 cortical area, induced by conditioned fear. Moreover, alpha-helical CRF((9-41)) increased the concentration of GABA in the amygdala of fear-conditioned rats. Altogether, the present data confirm and extend previous data on the integrative role of CRF in the central, anxiety-related, behavioral and biochemical processes. The obtained results underline also the role of frontal cortex and amygdala in mediating the effects of CRF on the conditioned fear response.

Corticotropin releasing factor receptors and their ligand family.[Pubmed:10816663]

Ann N Y Acad Sci. 1999 Oct 20;885:312-28.

The CRF receptors belong to the VIP/GRF/PTH family of G-protein coupled receptors whose actions are mediated through activation of adenylate cyclase. Two CRF receptors, encoded by distinct genes, CRF-R1 and CRF-R2, and that can exist in two alternatively spliced forms, have been cloned. The type-1 receptor is expressed in many areas of the rodent brain, as well as in the pituitary, gonads, and skin. In the rodent, one splice variant of the type-2 receptor, CRF-R2 alpha, is expressed mainly in the brain, whereas the other variant, CRF-R2 beta, is found not only in the CNS, but also in cardiac and skeletal muscle, epididymis, and the gastrointestinal tract. The poor correlation between the sites of expression of CRF-R2 and CRF, as well as the relatively low affinity of CRF for CRF-R2, suggested the presence of another ligand, whose existence was confirmed in our cloning of urocortin. This CRF-like peptide is found not only in brain, but also in peripheral sites, such as lymphocytes. The broad tissue distribution of CRF receptors and their ligands underscores the important role of this system in maintenance of homeostasis. Functional studies of the two receptor types reveal differences in the specificity for CRF and related ligands. On the basis of its greater affinity for urocortin, in comparison with CRF, as well as its brain distribution, CRF-R2 may be the cognate receptor for urocortin. Mutagenesis studies of CRF receptors directed toward understanding the basis for their specificity, provide insight into the structural determinants for hormone-receptor recognition and signal transduction.

Alpha-helical CRF(9-41) prevents anxiogenic-like effect of NPY Y1 receptor antagonist BIBP3226 in rats.[Pubmed:9427342]

Neuroreport. 1997 Nov 10;8(16):3645-7.

We reported previously that the neuropeptide Y (NPY) Y1 receptor antagonist, N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine amide (BIBP3226) has an anxiogenic-like effect in the elevated plus maze test in rats. In this study we investigated the effect of the corticotropin-releasing factor (CRF) receptor antagonist, alpha-helical-CRF(9-41) (alpha-h-CRF) on this response. BIBP3226 (5 microg, i.c.v.) induced an anxiogenic-like effect, which was blocked by pretreatment with alpha-h-CRF at a concentration (1 microg, i.c.v.) which alone failed to affect the elevated plus maze performance. Thus, the anxiogenic effect of a selective Y1 receptor blocker was prevented by the blockade of CRF receptors, suggesting antagonistic effects of endogenous NPY and CRF in shaping the response to novelty.

Potentiation of acoustic startle by corticotropin-releasing factor (CRF) and by fear are both reversed by alpha-helical CRF (9-41).[Pubmed:2610824]

Neuropsychopharmacology. 1989 Dec;2(4):285-92.

A series of experiments were performed to investigate the effects of alpha-helical CRF [9-41] (AHCRF), a structural analogue and functional antagonist of corticotropin-releasing factor (CRF), on CRF- and fear-potentiated acoustic startle amplitude. Intracerebroventricular (ICV) administration of the CRF antagonist AHCRF reversed the potentiation of startle amplitude that was produced by ICV administration of CRF (1.0 micrograms). Doses of AHCRF that antagonized CRF-potentiated startle amplitude also reversed the potentiation of startle produced by conditioned "fear" but failed to lower startle baseline or antagonize strychnine-potentiated acoustic startle. These results suggest that CRF and "fear" may potentiate acoustic startle through overlapping neural substrates.