Evidence suggests that 5-HT(1A) receptors are involved in the behavioral effects of antidepressant drugs, such as fluoxetine, and in the anxiolytic drugs such buspirone, although there is some controversy regarding the contribution of presynaptic and postsynaptic 5-HT(1A) receptors. Although 5-HT(1B) receptors are also located both presynaptically and postsynaptically, there has been little information regarding the involvement of these receptors in antidepressant or anxiolytic behavioral effects, because of the existence of few selective agonists or antagonists. This research program will examine the involvement of 5- HT(1A) and 5-HT(1B) receptors in antidepressant and anxiolytic behavioral effects in mice using gene knockout strategies. The use of gene knockout strategy is proposed to study these behaviors because the endogenous manipulation of receptor expression may model genetic or environmental alterations in receptors which contribute to the development of depression and anxiety and gene knockout strategies can provide new effective neuropharmacological tools for examining the neural substrates underlying the effects of antidepressant and anxiolytic drugs on behavior. Proposed studies will generate mutant mice with constitutive deletion of the gene that produces either 5-HT(1A) or 5-HT(1B) receptors and the effects of such deletions will be characterized using a series of biochemical and behavioral tests. The forced swimming test, a behavioral test that predicts the efficacy of many antidepressant treatments, will be used to compare the behavior of wild-type and mutant mice to establish baseline differences or differences in the antidepressant behavioral effects produced by fluoxetine, desipramine or 8-OH-DPAT. Behavioral tests associated with anxiolytic drug effects, such as conditioned defensive burying behavior or avoidance exploratory behavior, will be used to compare the behavior of wild-type and mutant mice on tests associated with anxiety. Additional studies will develop a tetracycline-inducible system to generate mice in which 5-HT(1A and 5-HT(1B) receptors can be manipulated in the adult. In addition, tissue-specific knockout of presynaptic 5- HT(1A) and 5-HT(1B) receptors will enable the relative role of presynaptic and postsynaptic receptors to be discriminated in behavioral tests associated with depression and anxiety. These studies will provide important information on behavioral consequences produced by targeted genetic manipulations of receptor systems known to be associated with antidepressant and anxiolytic psychotherapeutic drugs.
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