Corticotrophin releasing factor CRF

Swerdlow N. R., Koob G. F. (1985). Separate neural substrates of the locomotoractivating properties of amphetamine, heroin, caffeine and corticotrophin releasing factor (CRF) in the rat. Pharmacol. Biochem. Behav. 23, 303-7. 

Neuropeptides are often grouped by their structural similarity or tissue source. Among these are the hypothalamic releasing factors (e.g., corticotrophin-releasing factor [CRF], thyrotropin-releasing hormone), anteior pituitary hormones (e.g., adrenocorticotrophic hormone [ACTFI], follicle-stimulating hormone [FSFI]), and posterior pituitary hormones... 

Recent in vitro hybridization studies in the rat have demonstrated that typical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the synthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid synthesis inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRF) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development. 

Figure 18.2. Endocrine-immune inter-relationship in normal subject. The hypothalamic-pituitary-adrenal (HPA) axis is a feedback loop that includes the hypothalamus, the pituitary and the adrenal glands. The main hormones that activate the HPA axis are corticotrophin releasing factor (CRF), arginine vasopressin (AVP) and adrenocorticotrophic hormone (ACTH). The loop is completed by the negative feedback of cortisol on the hypothalamus and pituitary. The simultaneous release of cortisol into the circulation has a number of effects, including elevation of blood glucose for increased metabolic demand. Cortisol also negatively affects the immune system and prevents the release of immunotransmitters. Interference from other brain regions (e.g. hippocampus and amygdala) can also modify the HPA axis, as can neuropeptides and neurotransmitters.

The effect of stress on the endocrine and immune systems depends upon its duration and severity. Following acute stress, the rise in ACTH in response to the release of corticotrophin releasing factor (CRF) from the hypothalamus results in a rise in the synthesis and release of cortisol from the adrenals. The increase in the plasma cortisol concentration results in a temporary suppression of many aspects of cellular immunity. Due to the operation of an inhibitory feedback mechanism, stimulation of the central glucocorticoid receptors in the hypothalamus and pituitary causes a decrease in the further release of CRF, thereby decreasing the further... 

Figure 18.3. Endocrine-immune inter-relationship in depression. In depression, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated with a down-regulation of its negative feedback controls. Corticotrophin releasing factor (CRF) is hypersecreted from the hypothalamus and induces the release of adrenocortico-trophic hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

Q4 Glucocorticoid secretion is controlled by the hypothalamus and anterior pituitary gland. Corticotrophin releasing factor (CRF) is produced in the hypothalamus and travels in the hypophyseal portal blood vessels to the anterior pituitary to release ACTH (adrenocorticotrophic hormone). There is a daily (circadian) rhythm in CRF and ACTH secretion, with a peak in the morning between 7 and 9 a.m. and a low point during the night. 

For example, the corticotrophin releasing factor (CRF) receptor patent was held by Neurocrine, and development of candidate molecules by others was thereby effectively inhibited. 

CORTICOTROPHIN-RELEASING FACTOR RECEPTOR ANTAGONISTS inhibit the actions of agents related to corticotrophin-releasing factor (CRF). Two subtypes of receptor, CRF, and CRFj. have recently been identiffed and cloned, and there is interest in these as therapeutic targets. See CORTICOTROPHIN-RELEASING FACTOR RECEPTOR AGONISTS. 

Corticotrophin-releasing hormone (CRH corticotrophin-releasing factor. CRF) controls release of corticotrophin (adrenocorticotrophic hormone. ACTH). which in turn controls the release of corticosteroids from the adrenal glands. See corticotrophin-releasing factor RECEPTOR agonists CORTICOTROPHIN-RELEASING FACTOR RECEPTOR ANTAGONISTS. 

I Given the role of the lypothalaniic-pituitaiy-adrenal (HP A) axis in depression, corticotrophin-releasing factor (CRF) receptors (CRFi, CRF2) antagonists are currently under clinical evaluation as antidepressants. 

Fig. 194. Three transverse sections through the cerebellum of the cat showing corticotrophin releasing factor (CRF)-like immunoreactivity in climbing fibers in the molecular layer (radial lines) and mossy fibers (dots) in the granular layer. Note corresponding positions (arrows) of strongly labelled climbing fibers and mossy fibers (arrows). Abbreviations CR I, II, Crus I and II FL, flocculus LS, simple lobule NIP, posterior interposed nucleus NL, lateral cerebellar nucleus NM, medial nucleus PFL, paraflocculus PML, paramedian lobule I-X, lobules I-X of Larsell. Cummings (1989).

Fig. 195. Diagrammatic representation of the location of parasagittal zones defined by dense collections of corticotrophin releasing factor (CRF)-immunoreactive axons in sections of the cerebellum of Saimiri sciureus. Black areas in indicate zones in which a high density of labelled axons was evident in the molecular layer of each folium. The sparse stipple indicates the remaining molecular layer with its moderate density of labelled axons. The dense stipple indicates the location of the granular layer, and unshaded areas indicate the location of white matter. Cerebellar lobules are indicated with Roman numerals. Cha and Foote (1988).

Fig. 197. Optokinetically induced increase in corticotrophin releasing factor (CRF) mRNA in caudal dorsal cap of the inferior olive of the rabbit revealed by darkfield photomicrograph of an emulsion-coated brain-stem section. The rabbit received 37 hr of binocular optokinetic stimulation in the posterior to anterior direction with respect to the left eye, causing a 360% increase in levels of CRF mRNA in the right dorsal cap. A,B. Bright-field and dark-field views of the same tissue section are shown. The finer spatial resolution of the emulsion demonstrates clustering of silver grains over individual olivary neurons. Scale bar = 200 fim. (Barmack and Young, 1990)...

Fig. II. VIP and CRF in the MOB. Photomicrographs through MOB showing cells labeled with an antibody to vasoactive polypeptide (VIP) in A and corticotrophin releasing factor (CRF) in B. The cells in A are probably Van Gehuchten cells while those in B are mitral cells. Bar in B, 100 //m.

Projections to the hypothalamus suppress hypothalamic release of corticotrophin-releasing factor (CRF),i which is known to increase the firing rate of the locus ceruleus as well as the sensation of fear,i i a phenomenon found in long-term treatment with SSRIs. 

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