We plan to continue our studies on the action of antidepressant drugs on the regulation of recognition and action function of the norepinephrine (NE) receptor coupled adenylate cyclase system in brain. Since atypical antidepressants (e.g. fluoxetine, alaproclate, alprazolam) do not or not consistently alter the sensitivity of the NE sensitive adenylate cyclase or the density of its Beta-adrenoceptor subpopulation in normal animals, we propose to study whether or not these atypical antidepressants interfere with the regulation of the NE receptor coupled adenylate cyclase system under conditions of changed neurohormonal sensitivity and density of Beta-adrenoceptors or of Beta-adrenoceptors which are, as a consequence of serotonergic denervation, resistant to down-regulation by DMI. Our proposed studies on pineal N-acetyltransferase activity and Beta-receptor mediated glycogenlysis will generate answers to the question of whether or not the drug induced changes in the sensitivity of the NE receptor coupled adenylate cyclase system are reflected in a net deamplification or net amplification, respectively, of the NE signal. Taking advantage of the marked antidepressant induced changes in sensitivity of the NE receptor coupled adenylate cyclase, we will study the consequences of such changes on cyclic AMP dependent protein kinase activity and cyclic AMP dependent phosphorylation of proteins of synaptic membranes. Since phospholipids play a key role in the integrity of cell membranes, the activity of membrane bound enzymes and receptor mechanisms, we intend to examine the role of phosphilipid methylation in the process of desensitization of the NE sensitive adenylate cyclase by antidpressants and of the apparent """"""""uncoupling process"""""""" of Beta-adrenoceptors in brain tissue from animals lesioned with 5,7,-dihydroxytryptamine. The long term objective of our studies is to gain a molecular understanding of the complex aminergic and endocrine regulation of central Beta-adrenoceptor function and its relation to the pharmacotherapy and pathophysiology of affective disorders.
Showing the most recent 10 out of 24 publications
