Grant: Operating Grant

Antidepressant drug research has traditionally been guided by the notion that the therapeutic efficacy of these agents derives from their capacity to correct neurochemical imbalances in serotonergic and/or noradrenergic neurotransmission. Despite the fact that we still do not understand how modifying monoamine levels may translate into antidepressant action, drug design of currently available antidepressants is nonetheless based on this mechanism of action. As a result, all antidepressants have similar shortcomings: 1) reduced side-effects but sub-optimal therapeutic efficacy, 2) dangerously long delays in therapeutic response (2-4 weeks), and 3) inability to alter the course of the illness; most patients relapse subsequent to drug withdrawal. We have recently observed that direct stimulation of the serotonergic 4 receptor (5-HT4R) can produce behavioral, electrophysiological, cellular and biochemical changes predictive of antidepressant action. More importantly, these changes are observed after only three days of treatment as opposed to the 2-4 weeks necessary with currently-available antidepressants. One of the behaviors that is reversed by 5HT4R stimulation is anhedonia, which is defined as a reduction in the capacity to experience reward (pleasure). Understanding how stimulation of this receptor sub-population leads to fast antidepressant action has the potential to be a significant breakthrough in the treatment of a serious mental disorder. We propose to combine biochemical, immunohistochemical, cellular, pharmacological and behavioral approaches to understand where and how stimulation of 5HT4Rs leads to this unusually fast antidepressant effect. In addition to elucidating the mechanisms of action of 5HT4R agonists, results of the proposed research may lead to the rational design of fast-acting, more effective antidepressants.