28 Thus, it seems reasonable to conclude that the hypersecretion of Cortisol in patients with VX-689 concentration depression or dementia may at least be partly a consequence of an increased activation of the HPA axis by AVP. Additional evidence for the change in the functional activity of the pituitary gland is provided by the finding that the adrenals and the pituitary are enlarged in those with depression,29,30 Inhibitors,research,lifescience,medical these changes being associated with a hypersecretion of CRF.31 Furthermore, the density of the CRF receptors in the

frontal cortex are reduced, presumably as a consequence of the hypersecretion of CRF.32,33 The hypersecretion of CRF would appear to be a state, rather than a trait, marker of depression.34 If hypercortisolemia is a common feature Inhibitors,research,lifescience,medical of major depression and some types of dementia, it would be anticipated that immunosuppression would

be a common feature of these conditions. However, it is apparent that both immunosuppression (for example, of natural killer cell [NKC] activity) and immune activation (for example, macrophage activation) are common features of depression. One possible explanation is that an increased vulnerability to environmental stress, which is a Inhibitors,research,lifescience,medical common feature of both depression and dementia,35 elicits a bidirectional, homeostatic interaction between the endocrine and immune systems. Thus, CRF has been associated with humoral activation that results in an increased release of Inhibitors,research,lifescience,medical proinflammatory cytokines. By activating the HPA axis, proinflammatory cytokines not only further release CRF, but also lead to glucocorticoid resistance, thereby impairing the regulatory feedback mechanism. Conversely, the increase in the concentration of plasma Cortisol, together with the increased sympathetic activity that is a normal feature of the stress response, suppresses NKC and T-cell replication. There is evidence that activation of the β-adrenoceptors on the NKC membrane, and which results in the decrease in activity of the NKCs, occurs Inhibitors,research,lifescience,medical independently of the activation of the HPA axis.35 Clearly the interaction between the immune system and the HPA axis is both complex and interdependent.

In the past 20 years, attention has focused on changes in the hypothalamic-pituitary-adrenal axis, together with the biogenic amine neurotransmitters noradrenaline, serotonin, and, to a lesser extent, dopamine.36,37 More recently, however, it has become apparent that both major depression and chronic stress PD184352 (CI-1040) result in more persistent structural changes in the brain as a consequence of the decrease in the synthesis of neurotrophic factors, such as BDNF and the antiapoptotic factor bcl-2.38 These changes are attributed to the chronic increase in brain glucocorticoids that arise due to the desensitization of central glucocorticoid type 2 receptors that occur as a consequence of the reduction in the inhibitory feedback mechanism.