The broad, long-term objective of this proposal is to elucidate the neuropsychopharmacological actions of inhibitors of Type IV cyclic AMP phosphodiesterase (PDE), which may represent a new class of antidepressant drugs. Experiments will be carried out to assess the effects of these drugs, as well as inhibitors of other cyclic AMP isozymes, in two behavioral models that have been shown to be sensitive to antidepressant drugs; behavior maintained under a differential-reinforcement-of-low-rate schedule and forced-swim behavior. The neuropharmacological mechanisms mediating behavioral activity will be assessed. In particular, it will be determined whether inhibition of Type IV PDE enzymatic activity or interaction with the high-affinity rolipram binding site is more closely associated with antidepressant-like behavioral effects. In addition, experiments will be carried out to determine whether athe level of noradrenergic activity in the brain regulates Type IV PDE, its sensitivity to pharmacological inhibition, the high-affinity binding of 3H-rolipram, and the antidepressant-like behavioral effects of Type IV PDE inhibitors. This will be accomplished by determining the effects of noradrenergic lesions on Type IV PDE activity and on the behavioral and neuropharmacological effects of Type IV PDE inhibitors. Experiments will be carried out to determine whether noradrenergic regulation of Type IV PDE is mediated by stimulation of beta adrenergic receptors by endogenous norepinephrine. This will be accomplished by determining the effects of chronic blockade of beta adrenergic receptors, by infusion of propranolol, on the activity of Type IV PDE and on the behavioral and neuropharmacological effects of Type IV PDE inhibitors. The results of the proposed experiments will; 1) show whether Type IV PDE inhibitors as a class possess antidepressant-like activity and whether these actions also are observed with selective inhibitors of other cyclic AMP PDE isozymes; 20 begin to elucidate the neuropharmacological mechanisms mediating antidepressant activity of rolipram and related drugs; 30 reveal whether the Type IV PDE is regulated transynaptically as a function of the level of noradrenergic innervation or stimulation; and 4) show whether regulation of Type IV PDE by noradrenergic neurons is mediated by beta adrenergic receptors. The data obtained will elucidate the interactions among noradrenergic neurons, beta adrenergic receptors, and Type IV PDE. Since all three appear to be neuropharmacological substrates for antidepressant drugs, the findings may be relevant to the understanding of the pathophysiology of depression and its pharmacotherapy.
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