5HT2A serotonin receptors represent a major site of action for atypical antipsychotic drugs, antidepressants and hallucinogens. Long-term treatment with a variety of 5HT2A receptor agonists and antagonists leads to down-regulation and altered trafficking of 5HT2A receptors in vitro and in vivo. The goal of this grant is to understand the molecular and cellular mechanisms by which 5HT2A receptors are regulated by alterations in their targeting and trafficking. To accomplish this goal, five specific aims are proposed. The first specific aim proposes to identify proteins which interact with the 5HT2A receptor using the yeast-two-hybrid method. The second specific aim proposes to characterize the binding of accessory proteins such as MAP-1A and arrestin to intracellular regions of the 5HT2A receptor. The third specific aim proposes to determine how binding of these accessory proteins modulates the trafficking and targeting of 5HT2A receptors in cortical neurons in vitro. The fourth specific aim proposes to determine the mechanisms responsible for agonist- and antagonist-induced internalization of 5HT2A receptors while the fifth specific aim proposes to determine if arrestins are involved in both agonist- and antagonist-induced endocytosis of 5HT2A receptors. Because a large number of drugs used in treating schizophrenia and depression mediate their actions by inducing a down-regulation of 5HT2A receptor number, these studies could clarify the mechanism of action of these psychiatrically important drugs. It is also possible that novel treatment strategies for disorders such as hallucinogen-induced psychosis may come from the basic studies outlined in this application. Finally, novel insights into the mechanism by which receptors are regulated at the cellular and molecular levels will be obtained with the proposed studies.
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