The relationship of endogenous depression to abnormal presynaptic alpha-2 adrenoreceptor function in the human brain is investigated. Human studies involve the use of blood platelet membrane alpha-2 adrenoreceptors to reflect the status of brain cell response (behavioral measures) in depressed patients before, during, and after antidepressant drug or electroconvulsive therapy treatment. The specific binding of tritium labeled clonidine and yohimbine is used to assess the alpha-2 adrenoreceptor function in human platelet membranes and changes in noradrenergic receptors in rat brain neuronal membranes. Mechanisms of down regulation (subsensitivity) of presynaptic alpha-2 receptors are studied by examining various modes of norepinephrine release from rat brain tissues after acute and chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors, or neuroleptics.