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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA012923-09
Application #
8075604
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
9
Fiscal Year
2010
Total Cost
$426,045
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Gregorio, G Glenn; Masureel, Matthieu; Hilger, Daniel et al. (2017) Single-molecule analysis of ligand efficacy in ?2AR-G-protein activation. Nature 547:68-73
Sensoy, Ozge; Weinstein, Harel (2015) A mechanistic role of Helix 8 in GPCRs: Computational modeling of the dopamine D2 receptor interaction with the GIPC1-PDZ-domain. Biochim Biophys Acta 1848:976-83
Johner, Niklaus; Mondal, Sayan; Morra, Giulia et al. (2014) Protein and lipid interactions driving molecular mechanisms of in meso crystallization. J Am Chem Soc 136:3271-84
Mondal, Sayan; Khelashvili, George; Johner, Niklaus et al. (2014) How the dynamic properties and functional mechanisms of GPCRs are modulated by their coupling to the membrane environment. Adv Exp Med Biol 796:55-74
Perez-Aguilar, Jose Manuel; Shan, Jufang; LeVine, Michael V et al. (2014) A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2. J Am Chem Soc 136:16044-54
Mondal, Sayan; Khelashvili, George; Weinstein, Harel (2014) Not just an oil slick: how the energetics of protein-membrane interactions impacts the function and organization of transmembrane proteins. Biophys J 106:2305-16
Moreno, Jose L; Holloway, Terrell; Rayannavar, Vinayak et al. (2013) Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice. Neurosci Lett 536:69-73
Mondal, Sayan; Johnston, Jennifer M; Wang, Hao et al. (2013) Membrane driven spatial organization of GPCRs. Sci Rep 3:2909
Moreno, José L; Holloway, Terrell; Umali, Adrienne et al. (2013) Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice. Psychopharmacology (Berl) 225:217-26
Moreno, José L; Muguruza, Carolina; Umali, Adrienne et al. (2012) Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem 287:44301-19

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