Why serotonergic hallucinogens such as LSD have unique neuropsychological effects remains afundamental question for neurobiology relevant to drug abuse, psychiatry and neuropharmacology. Theprimary target for hallucinogens is the serotonin 5HT2A receptor (5HT2AR). The neuronal signaling eventsand circuitry responsible for their unique effects in comparison with closely related non-hallucinogens havenot been resolved. In vitro, hallucinogens and other 5HT2AR agonists show agonist-directed signaltrafficking, i.e.they differentially activate 5HT2AR signaling pathways. We developed a high-throughputquantitative genomics-based approach called transcriptome fingerprinting (TFP) that reflects complexsignaling responses, and our studies are consistent with hallucinogen signal trafficking in vivo and in primarycultured 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 providethe basis to investigate the molecular target, signaling mechanisms and neurons modulated byhallucinogens. In order to elucidate the cellular and molecular mechanisms underlying hallucinogensignaling specificity, we will pursue two aims. We will use in vitro studies to investigate the mediators ofhallucinogen-specific signaling in neurons, the role of 5HT2AR structure on hallucinogen-specific signalingand the presence and functional role of 5HT2AR-mGlu2 receptor complexes. In mouse, we will study theidentity of hallucinogen-responsive neurons anatomically and will collaboratively study a variety of mousemodels to test hypotheses about the target and mechanism of hallucinogens in vivo. These studies will usethe unique synergy of this PPG to test and refine specific hypotheses for the mechanism of action ofhallucinogens.
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