Page - (000134) - in Biomedical Chemistry: Current Trends and Developments

imply that dysregulation of a stress-related system is primary and not simply a consequence of depressed mood (Wong, 2000; Wong & Licinio, 2001). Thus, chronic uncontrollable stress may promote the onset of MDD and a shift towards environment withdrawal (Clark & Beck, 2010). 2.2.2 The Stress Response A series of physiological and behavioral stereotyped responses, which have been evolutionary developed to promote survival, characterize our reaction to danger. That reaction, popularly known as the “fight-or- flight response”, is better reflected by the term “fight, flight, freeze or fawn response” and includes increased heart rate and defensive/offensive behaviors, which are modulated by an extensive and complex circuitry that prepares the cardiovascular, musculoskeletal, endocrine, metabolic and immune systems to deal with threating events, and inhibits certain physiological functions, such as reproduction, sleep, foraging/digestion and growth, which are dispensable until the cessation of the short-term acute stress (Cahill & McGaugh, 1998; LeDoux, 1995). The core stress system includes the CRH, the locus ceruleus-norepinephrine (LC-NE), and the immune systems. This core system detects and monitors the intensity and duration of the stress response, promotes arousal, modulates the limbic system and the cortical functions in order to favor survival. While the stress response to acute, short-term stress is physiological and adaptive to promote survival during threatening situations, the persistent stress response to long-term chronic stress is generally maladaptive and harmful, as it dysregulates the stereotyped stress response (McEwen, 1998). 2.2.2.1 The CRH System and the Stress Response Four related ligands (CRH, urocortin I, II and III), two receptors (CRHR1 and 2), and a binding protein (CRHBP) that acts as an endogenous antagonist have been recognized in this system (Aubry, 2013; Heinrichs, 1997). For the purpose of this chapter, we will focus on the CRH and the