The focus of the research is on elucidating noradrenergic mechanisms involved in antidepressant activity. The research plan describes experiments to test two overall hypotheses. First, it is hypothesized that beta-2 adrenergic autoreceptors are present on noradrenergic terminals in the central nervous system and that these receptors are involved in mediating the antidepressant-like behavioral effects of centrally acting beta adrenergic agonists. Second, it is hypothesized that atypical/beta-3 adrenergic receptors are present in the central nervous system and that stimulation of these receptors produces antidepressant-like effects on behavior. These hypotheses will be tested using both behavioral and neuropharmacological techniques. The specific procedures to be employed include examination of drug effects on behavior maintained under a differential-reinforcement-of-low-rate operant schedule, measurement of drug-receptor interactions using receptor and adenylyl cyclase assays, and assessment of norepinephrine release in vitro using superfusion and in vivo using microdialysis. The second, related area of research, which is not a formal component of the research plan, involves the examination of the antidepressant potential of inhibitors of Type IV phosphodiesterase and the study of how the activity of this enzyme and its sensitivity to pharmacological inhibition are regulated by central noradrenergic neurons.
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