The long-term goals of our studies are to identify the molecular mechanisms of desensitization of serotonin 2A (5-HT2A) receptor signaling. Adaptive changes in post-synaptic 5-HT2A receptor signaling underlie the mechanism of action of several drug treatments for psychiatric disorders including anxiety, schizophrenia, depression, and bipolar disorder. Paradoxically, chronic treatment with both 5-HT2A receptor agonist such as DOI and antagonists including olanzapine desensitize 5-HT2a receptor signaling. Atypical antipsychotics are 5-HT2A receptor antagonists. Although these drugs are widely used, significant numbers of individuals are refractory to drug therapy and their effectiveness is delayed about 2 weeks after treatment is initiated. To help to resolve these problems, we plan to investigate the mechanisms by which 5-HT2A receptor signaling is desensitized. We will examine the mechanisms of desensitization of 5-HT2A receptor signaling induced with 5-HT2A receptor agonists (Aim 1), 5-HT2a receptor antagonists (Aim 2) and regulators of G protein signaling (RGS) proteins (Aim 3) in cells in culture and in vivo. Our hypothesis is that Jak/Stat signaling is critical for antagonist-induced desensitization, while the receptor-G protein functioning is reduced in agonist-induced desensitization of 5-HT2.A receptor signaling. We will test the hypothesis that RGS proteins also cause adaptive changes leading to 5-HT2A receptor desensitization via mechanisms in addition to acting as GTPase-activating proteins (GAPs). Neuroendocrine responses to 5-HT2A receptor-stimulation will be used as an index of desensitization of 5-HT2A receptor signaling in vivo. A major advantage of the neuroendocrine challenge tests is that the results obtained in experimental animals can be rapidly applied to humans since these tests can be performed in humans. Ultimately the purpose of these studies is to identify new targets for therapeutic intervention for psychiatric disorders currently treated with drugs that alter 5-HT2A receptor signaling. By understanding the mechanisms involved in neuroadaptation, new approaches can be developed to reduce the delay in therapeutic response and treat individuals refractory to current therapies
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