This is a 5-year revised renewal application, for Periods 18-22, to continue studies of HPA axis hyperactivity in major depression. Our hypothesis, based on our and others' data, is that this is a central nervous system (CNS) hormonal- and autonomic-driven HPA hyperactivity, as reflected in a reduced ACTH response to CRH administration (secondary to cortisol negative feedback), adrenal hypertrophy, and possibly adrenal hyperresponsivity to ACTH administration as well. We further hypothesize that CNS cholinergic mechanisms are one important factor that drives the HPA axis. To elucidate the hormonal component, at the CNS level we plan to continue testing our hypothesis that HPA axis responsiveness to low- dose cholinergic challenge will be greater in major depressives than in individually matched normal controls. At the pituitary level, using metyrapone blockade of cortisol synthesis, we plan to test our hypothesis that, lacking cortisol negative feedback, the pituitary will be more responsive to CRH in patients than in controls. At the adrenal level, we plan one additional low-dose ACTH/1-24 stimulation study to test our hypothesis that the sensitivity of the adrenal gland is greater in patients. Additionally at the cell-membrane level, we plan to continue pilot studies of the dose-response effect of cortisol on the structural ordering of model cell membranes and RBC and lymphocyte plasma membranes, as a test of the hypothesis that tissue insensitivity to cortisol may underlie the lack of Cushingoid features in hypercortisolemic depressives. hormone measures include plasma ACTH/1-39, ACTH/1-24 (immunoreactive ACTH), and cortisol, plus GH in some cholinergic stimulation studies and hCRH, metyrapone, 11-deoxycorticosterone, and 11- deoxycortisol in the metyrapone studies. We further hypothesize that HPA axis hyperactivity in depression is state-dependent, and that following treatment, the hormone measures will return to normal in a consistent manner. Thus, all patients are being tracked through their treatment and are being studied a second time when they are in remission and off medication for at least one month. The studies proposed herein should add to the evidence that HPA axis hyperactivity results from increased CNS stimulation of CRH production, and that this increase is related to cholinergic neurotransmission in the CNS. The findings should give further impetus to the study of CNS neurotransmitter regulation of HPA axis activity in major depression, stress states, and other conditions leading to increased HPA axis activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH028380-21
Application #
2890278
Study Section
Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
Program Officer
Meinecke, Douglas L
Project Start
1985-12-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
21
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Allegheny-Singer Research Institute
Department
Type
DUNS #
033098401
City
Pittsburgh
State
PA
Country
United States
Zip Code
15212