The goals of this proposal are to determine: a) the role of beta adrenergic receptors in hippocampal subregions in mediating antidepressant activity and the behavioral effects of noradrenergic antidepressants; and b) the relationship between changes in noradrenergic neurotransmission and the persistent behavioral effects that result from repeated treatment with noradrenergic antidepressants. To address these goals, four lines of investigation are proposed. First, it will be determined whether stimulation of beta-adrenergic receptors in subregions of the hippocampus produces antidepressant-like effects on behavior. This will be accomplished by determining the effects on DRL and forced-swim behavior of infusion of beta-adrenergic agonists and antagonists into subregions of the hippocampus (CA 1, CA2/CA3, dentate gyrus). Second, it will be determined whether beta-adrenergic receptors in subregions of the hippocampus mediate the behavioral effects of noradrenergic antidepressants. This will be accomplished by determining the ability of site-specific infusion of beta-adrenergic antagonists to block the effects of desipramine and reboxetine on DRL and forced swim behavior. Third, it will be determined whether the persistent behavioral effect on forced-swim behavior that occurs with repeated antidepressant treatment results from regulation of the norepinephrine transporter. This will be accomplished by comparing the dose-response and time-course of the behavioral effects with those for the regulation of the norepinephrine transporter produced by repeated treatment with desipramine or reboxetine. Fourth, it will be determined whether regulation of the norepinephrine transporter by repeated antidepressant treatment results in enhanced noradrenergic neurotransmission. This will be accomplished by comparing the dose-response and time-course of antidepressant-induced regulation of the norepinephrine transporter with those for increases in extracellular norepinephrine concentrations, measured using in vivo microdialysis. Completion of the proposed experiments will demonstrate the role that hippocampal beta-adrenergic receptors play in the mediation of antidepressant activity, particularly for those drugs thought to act via interactions with noradrenergic neurons. In addition, the manner by which adaptive changes in noradrenergic neurotransmission contribute to the development of persistent antidepressant effects will be elucidated. Overall, this work will provide new information relevant to the understanding of the pathophysiology and pharmacotherapy of depression. ? ?
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