Presynaptic receptors are important in the regulation of transmitter release from various neurons. The project is based upon the following hypotheses: 1) presynaptic alpha2 adrenergic receptors in the central nervous system are important sites for the pharmacological actions of psychotropic drugs, especially those agents which are used to treat endogenous depression and panic-anxiety disorder; 2) depressive disorders and anxiety disorders might be related to abnormal presynaptic alpha2 adrenergic receptor function; 3) the status of these receptors might be reflected by alpha2 adrenergic receptors on blood platelet membranes as well as by responses to physiological and pharmacological challenges. Functional changes in presynaptic alpha2 adrenergic receptors will be determined in 1) superfused, electrically stimulated rat brain slices and 2) isolated rat left atrial strips. The release of neurotransmitter during electrical stimulation of neurons in these preparations will be determined by mesuring a) the release of 3H-norepinephrine after preincubating the tissues with 3H-norepinephrine, b) the efflux of endogenous norepinephrine by a combination of high pressure liquid chromatography and electrochemical detection, c) changes in the responses of the isolated atrial muscle preparation, and d) the release of dopamine beta-hydroxylase. Simultaneously with the functional studies the specific binding of 3H-clonidine, 3H-yohimbine, 3H-prazosin and 3H-dihydroalprenolol to neuronal membranes isolated from various areas of the rat brain and to neuronal and non-neuronal membranes isolated from heart and vascular smooth muscle will be measured. Studies to determine functional changes in post-synaptic alpha2 adrenergic receptors will be carried out with isolated strips of rat tail artery. Changes in the number and/or affinity of alpha2 adrenergic receptors on human blood platelet membranes will be determined in depressed patients and patients with anxiety disorders before, during and after treatment, as well as in normal subjects and in patients with other psychiatric and non-psychiatric diagnoses. The specific binding of various agonist and antagonist ligands for the alpha2 receptor on platelet membranes will be measured to assess alpha2 adrenergic receptor function. In addition, changes in various cardiovascular parameters and in plasma catecholamine levels will be determined in these patients after physiological (assuming an erect position from a supine position) and pharmacological (intravenous yohimbine infusions) challenges.
