MONOAMINE RECEPTOR SENSITIVITY AND MENTAL ILLNESS

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The long-term objective of the proposed study is to examine the role of monoamine receptors in the etiology of affective illness and schizophrenia, and to examine if alterations in monoamine receptor sensitivity are related to the mode of action of antidepressant and antipsychotic drugs. In examining the role of monoamine receptors, it is proposed that both the function and the number of these receptors be studied in the peripheral tissue obtained from hospitalized psychiatric patients and normal controls. The receptors to be studied are beta-adrenergic receptors in the human leukocytes and alpha-adrenergic receptors in human platelets. The biochemical function of the receptors will be studied by determining the agonist stimulated cyclic AMP production of adenylate cyclase in leukocytes. The number and the affinity of beta-adrenergic receptors in human leukocytes will be studied by binding techniques using 125I-cyanopindolol (CYP), an adrenergic antagonist. Alpha2adrenergic receptors in platelets will be studied by binding with specific alpha-adrenergic agonist, 3H-clonidine. Since some reports indicate decreased beta-adrenergic receptor responsiveness in patients with depression, this project will examine the factors which may be associated with down regulation of beta-adrenergic receptors in human leukocytes. In particular, the role of altered levels of catecholamines such as epinephrine and norepinephrine (NE) in plasma and cortisol will be examined in these patients. The studies will examine if the down regulation of beta-adrenergic receptors is related to the pathophysiology of affective illness or if it is secondary to changes in the amine levels in the plasma. In order to examine the sites of down regulation we propose to study the three components of the adenylate cyclase, that is, the receptors, the g-protein, and the regulatory subunit of the adenylate cyclase in the human leukocytes. In order to examine the role of platelet alpha2adrenergic receptor, we will determine the density and the affinity of these receptors using 3H-clonidine. Since alpha2adrenergic receptors play a role in the release of NE, urinary and plasma levels of MHPG and other metabolites of NE will be determined as an index of NE turnover. These studies may help not only in the understanding of the biochemical etiology of mental illness but will also help in characterizing subgroups of patients, since it is known that neither depression nor schizophrenia consists of a homogenous population. It may thus be beneficial in the diagnosis and treatment of these patients.