This proposal examines behavioral measures of the functional status of specific transmitter systems in the hippocampi of rats following chronic antidepressants to elucidate the neurochemical substrates of their therapeutic actions. Clinically, most antidepressant drugs take 3 weeks of adminstration to alleviate depression. In animals, chronic antidepressants alter neurochemical, electrophysiological and, most consistently, ligand-binding measures of the functioning of central noradrenergic, serotonergic, and cholinergic systems. To more directly and specifically assess the behavioral relevance of these reported changes, I propose to examine the effects of acute and chronic antidepressants on the behavioral effects of hippocampal microinfusions of norepinephrine, serotonin, and the cholinergic agonist carbachol. Using a new behavioral pattern monitor which reveals quantitative and qualitative changes in locomotor activity and investigation, my laboratory has described dose-dependent behavioral effects specifically reflective of the activation of either beta-adrenergic or muscarinic-cholinergic synapses in the dentate gyrus of the hippocampus. Studies are proposed here to similarly characterize the effects of serotonin infusions with neurotoxin lesions of the raphe nuclei being used to confirm their specificity. The distribution of infusate and the extent of lesions will be assessed with fluorescence histochemistry and liquid chromatography with electrochemical detection. The functional status of the serotonergic, beta-adrenergic, and muscarinic-cholinergic inputs to the hippocampus will be assessed behaviorally after 1 or 21 daily oral treatments with 4 disparate antidepressants: desmethylimipramine; imipramine; tarzodone; and mianserin. Appropriate ligand-binding studies will be done on the hippocampi from the same rats to confirm the expected changes due to the antidepressants. These studies should establish the functional significance at a behavioral level of the ligand-binding changes induced by antidepressants, and increase our understanding of the brain mechanisms responsible for their therapeutic actions in humans.
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