It is well established that depression is associated with increased activity of the hypothalamic-pituitary-adrenal axis, as indicated by elevated urine, serum and cerebrospinal fluid cortisol levels. However, depressed patients fail to show the physiological effects of excess glucocorticoids (GCC), such as the stigmata of Cushing's disease. In addition, 50% of depressed patients have abnormal dexamethasone suppression test (DST) results (i.e., 1 mg dose of dexamethasone (DEX) fails to suppress serum cortisols less than 5.0 Mug/dl). Other hormones in non-suppressors, such as ACTH, prolactin and Beta-endorphin, are also resistant to DEX-induced inhibition. Since DST non-suppression is generally associated with increased basal serum cortisol levels, the chronically elevated cortisol levels may modify glucocorticoid receptor (GCCR) function. The objectives of this proposal are to clarify the molecular basis of the DST abnormality. We plan to test the hypothesis that the failure to suppress is due to an abnormality of the GCCR, specifically an insensitivity of the GCCR to DEX. This hypothesis will be tested via studies with lymphocytes from depressed patients and normal controls. Lymphocytes possess GCCR which can be quantified via 3H-triamcinolone (3H-TA) and whose function can be assessed by monitoring the ability of DEX in vitro and following in vivo administration to inhibit the mitogen-induced incorporation of 3H-thymidine into lymphocytes. Preliminary results suggest non-suppression with the DST correlates well with diminished responsiveness of lymphocytes to DEX-induced inhibition of 3H-thymidine incorporation following DEX administration in vivo and failure of DEX to cause a decrease in GCCR content in the cytosol of lymphocytes from non-suppressors, whereas a 39% decrease occurred in suppressors. Normal controls and depressed suppressors had a comparable response. Preliminary results indicate a positive correlation between post-DFX cortisol levels and the DEX-induced change in mitogen response and receptor levels. If our hypothesis is confirmed, it would provide further impetus for studying the lymphocyte as a model for central nervous system pathophysiology in major depression. It might also imply that GCCR subsensitivity is present throughout the tissues of major depressives (and other psychiatric patients) who are non-suppressors. If so, GCCR subsensitivity might affect biogenic amine and peptidergic activity in the brain, since neurons which elaborate these substances as neurotransmitters and neuromodulators have GCCR which influence processes such as synthesis, uptake and receptor sensitivity.
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