ABRAHAM et si HPA Axis, Stress & Orcadian Rhythm Hippocampus H P A A x i s Stress Circadian GR/MR mediated -ve feedback CORT GRsMRs there are excitatory and inhibitory afferents, including those containing 5-hydroxytryp- tamine (5-HT), noradrenaline, acetylcholine, and both excitatory and inhibitory amino acids, Qones, et al, 1987). The intrinsic autoregulatory mechanism plays a crucial role in the regulation of the HPA axis. The glucocorticoid receptors (GR) play a key role in this feed back mechanism. The endogenous Cortisol, by binding to the GR in the HPA axis tissues and the hippocam­ pus, acts as a potent negative regulator of HPA activity (Sapolsky, et al, 1986). This autoregulatory role of endogenous Cortisol via the GR is crucial to the maintenance of the intrinsic homeostasis of the HPA axis Qacobson, et al, 1991; Sapolsky, et al, 1986). The set point of pituitary feedback is determined by the hypothalamus acting through the hypothalamic releasing hor­ mones CRH and vasopressin. (Antoni, 1986; Vale, et al, 1983). Glucocorticoids act on both the pituitary corticotropes and the hypothalamic neurones that secrete CRH and vasopressin. A still higher level of feedback control is exerted by glucocorti­ coid responsive neurones in the hippocam­ pus that project to the hypothalamus and Ptguraa i k « M ID • » <m/Cfw mt 1548 Tkn* («) affect the activity of CRH hypophyseotropic neurones and in turn determine the set point of pituitary responsiveness to glucocorticoids (Sapolsky, et al, 1986). CORT (Cortisol in man, corticosterone in rats), in some respects the final product of the HPA axis, has both central and periph­ eral effects. It is lipid soluble and enter the brain through the blood-brain barrier (de Kloet, et al, 1993). CORT maintains basal activity of the HPA system. It also exerts rapid non genomic effects. CORT promotes co-ordination of circadian events, such as the sleep/wake cycle and food intake and is involved in processes underlying selective attention, integration of sensory informa­ tion and response selection. It facilitates an animals ability to cope with, adapt to, and recover from stress and promotes learning and memory processes (De Kloet, et al, 1998). CORT acts on both type 1 - min- eralocorticoid receptors (MR) and type 2 - glucocorticoid receptors (GR) (De Kloet, et al, 1998). MR have a relatively restricted distribution, being particularly expressed in the hippocampus. GR are more widely distributed, have a 10-fold lower affinity for CORT and therefore their activation, in contrast to MR, varies widely across the diurnal range of CORT concentrations. MR are saturated by basal levels of glucocorticoids, whereas GR are not satu­ rated under basal conditions, but approach saturation during peak phases of circadian rhythm and during stress. De Kloet and colleagues (De Kloet, et al, 1987; De Kloet, et al, 1998) have hypothesised that tonic influences of CORT are exerted via hippoc- ampal MRs, while the additional occupancy of GRs with higher levels of CORT mediates feedback actions aimed to restore balances in homeostasis. Role of HPA axis in t h e Pathophysiology of mood disorders HPA axis dysfunction in mood disorders is suggested by the findings that 20-24% of patients with unipolar depression are hypercortisolaemic (Young, et al, 2001). 27- 43% of mood disorder patients have an abnormal DST response (Rush, et al, 1996) and 80% of unipolar depressed patients have an abnormal response to the dex/CRH ,