69 Future studies will help identify whether this has NVP-BKM120 potential etiologic meaning in depression; also, it is likely that other genetic variations will be identified and investigated in similar fashion. Neuroendocrine systems The potential contribution of dysfunction of the endocrine system to the neurobiology of depression has long been recognized. Most research has focused on the hypothalamic-pituitary-adrenal (HPA)
Inhibitors,research,lifescience,medical axis and, to a lesser degree, on the hypothalamic-pituitary-thyroid (HPT) axis. HPA axis In vulnerable individuals, psychological and physiological stress has long been known to precipitate or worsen depressive episodes. The HPA axis is the primary neuroendocrine system responsible for coordinating
the mammalian stress response, and has thus been a major focus of research into the neurobiology of depression. Its major components include corticotropin-releasing factor (CRF), Inhibitors,research,lifescience,medical adrenocorticotropin hormone (ACTH) and glucocorticoids; Cortisol is the major glucocorticoid in humans. During the stress response, neurons in the paraventricular nucleus (PVN) of the hypothalamus release CRF into the hypothalamo-hypophysial portal system. CRF then stimulates adrenocorticotropin (ACTH) Inhibitors,research,lifescience,medical release from the anterior pituitary into the systemic circulation, which in turn stimulates the adrenal cortex to secrete Cortisol. Cortisol is responsible for many of the physiological changes associated with the stress response, and also provides negative feedback to the hypothalamus and pituitary to decrease synthesis and release of CRF and Inhibitors,research,lifescience,medical ACTH. Quite distinct from the HPA axis is the widespread CNS distribution of CRF and CRF receptors that includes several cortical, subcortical, and brain stem regions. Importantly, these CRF systems modulate the autonomic, immunologic, and behavioral responses to
stress.70 Two main CRF receptor subtypes Inhibitors,research,lifescience,medical have been identified (CRF1 and CRF2) which appear to have differential effects on behaviors related to mood and anxiety. CRF1 receptors have a high affinity for CRF, and are widely distributed in the CNS, and reduced anxiety in animal next models is associated with reduced activity of these receptors. In contrast, CRF2 receptors have a lower affinity for CRF, have a widespread distribution with limited overlap with that of CRF1 receptors, and reduced CRF2 activity has been linked with increased anxiety-like behaviors in animals.70,71 The HPA axis is abnormally active in patients with depression. CSF CRF concentrations are elevated in drug-free depressed patients compared with controls, and CRF mRNA expression and the number of CRF-containing neurons in the PVN are increased in depressed patients.72,73 CRF concentrations are elevated in the frontal cortex of depressed patients, and there is a corresponding reduction in CRF1 receptors in suicide victims in this area.74,75 Further, antidepressants modify CRF activity.