Behavioral and electrophysiologic studies suggest that the regulation of serotonin (5-HT) release may be involved in the clinical effects of new psychotherapeutic drugs, particularly 5-HT uptake inhibitors such as fluoxetine that are antidepressants and 5-HT(1A) receptor agonists such as buspirone that are anxiolytics and antidepressants. Evidence suggests that chronic administration of SSRIs produces desensitization of presynaptic 5-HT(1A) receptors that may account for, at least in part, the lag time between the initiation of drug treatment and the appearance of therapeutic effects. In addition, clinical studies suggest that coadministration of antagonists of 5-HT(1A) autoreceptors can potentiate the clinical effects of SSRIs. The new technique of in vivo microdialysis permits the release of 5-HT to be measured in discrete brain regions in awake unrestrained animals. This technique is ideally suited to directly study the ability of psychotherapeutic drugs to regulate the ability of presynaptic 5-HT(1A) receptors to modify 5-HT release and to determine whether altered 5-HT release is involved in their behavioral effects. The first goal of this project will be to establish the time course for the ability of SSRIs and MAOIs to regulate the release of 5-HT in the striatum and hippocampus by modifying the function of presynaptic 5-HT(1A) autoreceptors. Additional studies will examine the time course of recovery of 5-HT(1A) receptor sensitivity after the discontinuation of drug treatment. Radioligand binding studies will examine changes in the density of 5-HT(1A) receptors in the raphe that are coupled to G proteins using new selective ligands developed by this Program. Additional studies will examine the ability of chronic administration of 8-OH-DPAT to 1) modify the function of 5-HT(1A) autoreceptors that regulate 5-HT release in the striatum and hippocampus and 2) to evaluate changes in the ability of SSRIs to increase extracellular 5-HT after prior treatment. Finally, the ability of coadministration of antagonists that are selective for 5-HT(1A) and 5-HT(1B) receptors to modify the effects of SSRIs on extracellular concentrations of 5-HT after and chronic administration of SSRIs will be studied. The results of the proposed work should have important implications for our understanding of synaptic transmission in the brain and of the effects of psychotherapeutic drugs.
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