The proposed project will test the following hypotheses: 1) Endogenous depression might be related to abnormal presynpatic alpha2 adrenergic receptor function in the human brain, and the status of these receptors might be reflected by alpha2 adrenoreceptors on blood platelet membranes. 2) Antidepressant drugs and electroconvulsive therapy both might act by altering the function of alpha2 adrenoreceptors upon noradrenergic neurons in the brain. 3) Changes in platelet alpha2 receptor function during therapy will provide a valuable biomonitor of the therapeutic efficacy of antidepressant drug therapy. Changes in the number and/or affinity of alpha2 adrenergic receptors on human blood platelet membranes will be determined in depressed patients before, during and after treatment, in normal subjects and in patients with other psychiatric and non-psychiatric diagnoses. The specific binding of 3H-clonidine and 3H-yohimbine to platelet membranes will be used to assess alpha2 adrenoreceptor function. Diagnostic subtyping of depressed patients will be based on the Research Diagnostic Criteria as well as a variety of other diagnostic tests and procedures which include the Dexamethasone Suppression Test and sleep EEG parameters. In animal studies, functional changes in the regulation of noradrenergic neuronal activity by alpha2 adrenergic receptors caused by antidepressant drugs and procedures will be determined by the use of two different preparations: 1) superfused rat brain slices and 2) isolated rat left atrial strips. The release of norepinephrine during electrical stimulation of neurons in these preparations will be determined by measuring a) changes in the responses of the isolated muscle preparation, b) the efflux of endogenous neurotransmitter measured by a combination of high pressure liquid chromatography and electrochemical detection, c) the release of 3H-norepienphrine after incubating the tissues with 3H-dihydroxyphenylalanine and d) the release of dopamine beta hydroxylase, an enzyme which is released with norephinephrine but which is not taken back up into the neuron. Changes in the function fo postsynaptic alpha2 adrenergic receptors will be measured by the use of isolated strips of rat tail artery. The rat tail artery is a tissue rich in alpha2 adrenergic receptors. Functional changes in noradrenergic neurons will be correlated with changes in the binding of 3H-clonidine, 3H-yohimbine and other radiolabeled ligands to neuronal membranes isolated from various areas of the rat brain and to neuronal membranes isolated from the muscle preparations.
