Mouse models of chronic antidepressant response: Investigating mechanisms of delayed onset of therapeutic efficacy.

摘要

The successful use of antidepressant drugs in the treatment of depression and anxiety disorders is impaired by a great degree of nonresponsiveness, as well as a delayed onset of therapeutic efficacy in patients. The goal of this thesis was to determine the neurobiological mechanisms underlying the antidepressant response using novel mouse models of chronic antidepressant drug action. The first goal was to establish, in mice, behavioral responses to antidepressant drugs that emerge specifically following chronic administration to best emulate the slow emergence of therapeutic response in patients. We identified four behavioral effects of chronic antidepressant action in an innately fearful/anxious strain of mouse (BALB/cJ): reduced immobility in the forced swimming test (FST), reduced hyponeophagia in the novelty-induced hypophagia (NIH) paradigm, reduced anxiety-like behavior in the open field, and reversal of drug-induced deficits in prepulse inhibition. We then used pharmacological, genetic and radiological techniques to disrupt mechanisms hypothesized to underlie these behavioral effects. We determined that neither 5-HTIA nor 5-HT4 receptors mediate the behavioral response to chronic treatment with the selective serotonin reuptake inhibitor, fluoxetine, in the FST or NIH in BALB/cJ mice. We also found that these behavioral effects do not depend on adult hippocampal neurogenesis. I discuss these findings with respect to previously published results, and conclude that strain- and test-specific mechanisms of the antidepressant response are important to the identification of the multiple mechanisms that may contribute to the therapeutic effects in patients. Lastly, we have discovered that 5-HT4 receptor activation has potentially faster-acting, antidepressant-like effects. This finding achieves the goal of this thesis, which was to understand the underlying mechanisms of the delayed onset of therapeutic efficacy of antidepressant drugs in order to develop novel and faster-acting antidepressants to more efficiently and effectively treat patients. Whether this compound will be clinically effective will be interesting to determine. Overall, these findings make clear the complexity of the antidepressant response in mice, which likely extends to patients. It appears that multiple circuits in the brain, as well as receptor systems and brain regions contribute to the overall response to antidepressant drugs.