Hypersecretion of glucocorticoids occurs in depression and Alzheimer's disease. Recent studies, including our own, indicate that depression is also associated with decreases in lymphocyte glucocorticoid receptor (GR) number and function. The overall goal of this proposal is to compare the regulation of brain and lymphoid GR in response to a variety of modulatory influences to determine if lymphoid GR are indeed a valid model of neuronal GR regulation. The type II GR will be quantitated in neuronal (hypothalamus, hippocampus and frontal cortex) and lymphoid tissues (lymphocytes, thymus and spleen) as well as in the pituitary using the specific type II GR ligand,3H-RU 28362. GR measurements include the number (Bmax) and affinity (Kd) of the receptor, the activation capacity of the GR as determined by a DNA-cellulose assay and the molecular weight of the GR using affinity labelling techniques. GR messenger RNA (mRNA) will also be quantitated using a sensitive ribonuclease protection assay. The effect of experimental manipulations which approximate the biological abnormalities observed in depression will be assessed for their effect on the proposed GR measurements in the target tissues. Initially, increases in circulating corticosterone levels will be assessed for their effect on GR. Since decrease brain biogenic amine systems are involved in the etiology of depression, the next set of studies will examine the effect of depleting neuronal levels of serotonin (5-HT) or norepinephrine (NE) on GR regulation. The effect of various antidepressant treatments (ADT), including monoamine reuptake inhibitors, lithium, electroconvulsive shock monoamine oxidase inhibitors on basal GR measurements will be assessed. The ability of these ADT to normalize any GR changes induced by monoamine depletion regimens will also be determined. The physiological significance of any observed changes in brain GR number will be assessed in vivo using dexamethasone-induced suppression of serum corticosterone. If the proposed studies demonstrate that lymphoid GR faithfully reflect changes in neuronal GR then clinical usefulness of lymphocyte GR measurements in human disease states, such as depression and Alzheimer's disease will be greatly enhanced. These studies may also provide new insights into cellular and molecular mechanisms associated with antidepressant treatments which may involve GR. Fundamental information on the regulation and molecular neurobiology of GR will also be elucidated.
