Most antidepressants have a delayed onset of therapeutic efficacy. Specifically SSRIs and tricyclic antidepressants often require several weeks of administration to reach full clinical efficacy. The two main hypotheses which have been proposed to explain this delay is 1: a progressive desensitization of autoreceptors such as the 5-HT1A and 5-HT1B autoreceptors which initially limit the increase in serotonin produced by most antidepressants, and 2: growth related changes that may take place downstream of the increases in monoamines elicited by these drugs. Among these growth-related events much of the focus has been on dendritic growth in the hippocampus and other limbic structures such as the amygdala and the prefrontal cortex, and on the generation of new neurons in the hippocampus, a phenomenon termed neurogenesis. We have developed in the previous funding period three animal models that respond to chronic but not acute antidepressants: the novelty-suppressed feeding, novelty-induced hypophagia and chronic unpredictable stress paradigms. In addition we have developed new genetic strategies to conditionally ablate 5-HT1A autoreceptors as well as young hippocampal neurons. In this competitive renewal we propose to take advantage of these behavioral and genetic tools to accomplish the following goals:
Aim 1 : We will test the hypothesis that mice lacking the 5-HT1A and/or the 5-HT1B autoreceptors will respond faster to antidepressants.
Aim 2 : We will test the hypothesis that young hippocampal neurons are necessary for the behavioral effects of antidepressants.
Aim 3 : We will attempt to identify the 5-HT receptors which are responsible for the effects of SSRIs on neurogenesis and behavior. Specifically, we will test the hypothesis that 5-HT1A receptors located on hippocampal progenitors are necessary for the effects of chronic fluoxetine on neurogenesis and possibly on behavior. This proposal may therefore provide ideas for the generation of novel antidepressants that would directly target neurogenesis or mimic the properties of young hippocampal neurons. Due to the anatomic specificity of neurogenesis, such agents might be expected to have fewer side effects, in addition to a faster onset of therapeutic efficacy.
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