Page - (000135) - in Biomedical Chemistry: Current Trends and Developments

CRHR1, as both are widely distributed in the brain, and CRH has high affinity to CRHR1 and poor affinity to CRHR2. CRH is the key hypothalamic factor in the HPA axis, it stimulates the pituitary gland to release adrenocorticotropin hormone (ACTH) and indirectly regulates glucocorticoids secretion and its production in the adrenal cortex. Besides its critical role in the HPA axis, CRH plays multiple additional roles in the stress response; it is implicated in coordinating the behavioral, neuroendocrine, autonomic and neurovegetative aspects of the stress response; it is relevant in functions such as the activation the LC-NE system, the sympathetic nervous system, catecholamine synthesis in the adrenal cortex, fear-related behavior, and the inhibition of exploratory behavior, food consumption, and growth and reproduction functions (Chrousos & Gold, 1992; Gold, 1988a, 1988b). CRH also modulates anxiety behavior, as corroborated by findings in studies of mice lacking CRHR1, which display decreased anxiety (Smith, 1998) and of CRHR1 antagonists, such as Antalarmin, which is a non-peptide selective CRHR1 antagonist. Antalarmin administration results in inhibition of anxiety-like responses induced by stress and the promotion and establishment of conditioned fear (Deak, 1999; Habib, 2000). Antarlamin also appeared to prevent increases in circulating ACTH, NE, epinephrine, and cortisol levels (Habib, 2000). 2.2.2.2 The Locus Ceruleus Norepinephrine (LC-NE) System and Other Central Nervous System (CNS) Structures that Modulate the Stress System Located in the brainstem, the LC is a homogenous nucleus with the largest number of noradrenergic neurons in the brain that innervates the entire neuroaxis. LC neurons have synchronous spontaneous activity that provides a mechanism for large-scale NE release across the CNS in response to stimuli (Berridge & Waterhouse, 2003). The LC acts as the brain’s alarm system, after a stressful challenge there is strong activation of this system that provides a mechanism by which external and internal stimuli induce arousal and vigilance. Multiple stressors that activate the HPA axis, also engage the LC-NE system, and induce immediate-early gene expression and NE release (Cullinan, 1995). The