The goals are to explore the effect of antidepressants and other psychoactive compounds on the regulation of beta-adrenergic and serotoninergic responsiveness, with particular emphasis on receptor mechanisms. Emphasis will be given to the effects of beta-adrenergic agonists, when given repeatedly to rats, on central beta-responsiveness so as to provide a pre-clinical rationale for the evaluation of such drugs as antidepressants. Beta-agonists will be administered to the rats either systemically or by intracerebroventricular infusion, using Alzet minipumps. Beta-adrenergic responsiveness will be assessed by measuring the ability isoproterenol to raise the concentration of adenosine 3', 5'-monophosphate (cyclic AMP) in slices of cortex and cerebellum prepared from control or drug-treated rats. Highly selective beta-antagonists will be used so as to link the rise in cyclic AMP in the cortex to beta1 receptors and in the cerebellum to beta2 receptors. The molecular mechanisms responsible for agonist-induced changes in responsiveness will be studied by measuring agonist effects on the density of subtypes of the beta-receptor in different parts of the brain (using both in vitro ligand binding techniques and quantitative autoradiography) as well as the interaction of the beta receptor subtypes with the guanine nucleotide binding regulatory protein (N protein). Such studies will provide important information on agonist-induced regultion of central beta-adrenergic receptors and their linkage with the N protein in vivo. Similar methodology will be used to examine whether antidepressant-induced changes in central beta-responsiveness are influenced by the concurrent administration of thyroid hormone. Such data might provide an explanation for the observation that administration of triiodothyronine to depressed female patients hastens imipramine-induced recovery from depression. Studies with receptors for serotonin (5-HT) will focus on the 5-HT1 receptor with emphasis placed on the effect of antidepressant treatments and serotonin agonists on the subtypes of this receptor and its high affinity state. Receptor alterations could explain the effects of these drugs, when given repeatedly to rats, on central serotonin responsiveness. At present, there is no selective radioligand for the 5-HT1B receptor subtype. However, the piperidinyl derivative, RU 24969, is selective for this subtype, consequently, experiments are proposed to incorporate tritium into the molecule and then to assess whether it could be used as a radioligand selective for 5-HT1B receptors. Drug-induced effects on the high affinity state of the 5-HT1 receptor can be assessed by doing saturation experiments in the absence of GTP and analyzing the data using non-linear regression analysis with the aid of a computer.
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