Why serotonergic hallucinogens such as LSD have unique neuropsychological effects remains a fundamental question for neurobiology relevant to drug abuse, psychiatry and neuropharmacology. The primary target for hallucinogens is the serotonin 5HT2A receptor (5HT2AR). The neuronal signaling events and circuitry responsible for their unique effects in comparison with closely related non-hallucinogens have not been resolved. In vitro, hallucinogens and other 5HT2AR agonists show agonist-directed signal trafficking, i.e.they differentially activate 5HT2AR signaling pathways. We developed a high-throughput quantitative genomics-based approach called transcriptome fingerprinting (TFP) that reflects complex signaling responses, and our studies are consistent with hallucinogen signal trafficking in vivo and in primary cultured neurons. TFP profiles that correlate with behavioral responses in mice in conjunction with cutting- edge computational and genetic approaches developed by the Weinstein and Gingrich laboratories provide the basis to investigate the molecular target, signaling mechanisms and neurons modulated by hallucinogens. In order to elucidate the cellular and molecular mechanisms underlying hallucinogen signaling specificity, we will pursue two aims. We will use in vitro studies to investigate the mediators of hallucinogen-specific signaling in neurons, the role of 5HT2AR structure on hallucinogen-specific signaling and the presence and functional role of 5HT2AR-mGlu2 receptor complexes. In mouse, we will study the identity of hallucinogen-responsive neurons anatomically and will collaboratively study a variety of mouse models to test hypotheses about the target and mechanism of hallucinogens in vivo. These studies will use the unique synergy of this PPG to test and refine specific hypotheses for the mechanism of action of hallucinogens.
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