Hallucinogens are drugs of abuse with an apparently unique mechanism of action producing disturbances in thought, perception and mood. The mechanisms for these actions of hallucinogens are unknown, but their association with 5-HT/2A receptor activities is longstanding. Despite considerable progress in characterizing behavioral, physiological and pharmacological properties of serotonergic hallucinogens, the molecular signature underlying the hallucinogenic potential remains elusive. The exact role of the 5-HT2A receptor in hallucinogenesis also remains obscure. To eliminate these important gaps in knowledge and understanding, this Program Project Grant (PPG) addresses a continuum of interrelated questions about function and effects elicits by hallucinogens on various mutant constructs of the human 5-HT/2A receptor (h5-HT2AR) expressed in cultured cells and in whole animals, in a common structural context of 3D receptor models and ligand structures. The fundamental molecular level of understanding sought here for the mechanisms of action of hallucinogens also aims to enable future efforts in structure/based design of therapeutic modalities against their abuse. The PPG is organized around comprehensive computation modeling, dynamics simulation, and structure analysis and design in Project 1. Functional probing for distinct mechanisms in the effects of hallucinogens on signal transduction, gene expression and behavior will be carried out in Projects 2&3 with pharmacological, biochemical and behavioral approaches involving genetically modified constructs in cell systems and whole mice. All three Projects will take the basis of specific structural hypotheses. Examples include one that equalizes the efficacies of 5-HT and hallucinogens (e.g., LSD), one that alters the interaction of the receptor with G proteins (e.g., coupling to small mw G proteins), and one that exhibits agonist-independent stimulation of second messenger production. Structure-activity considerations for distinctive models of interaction of hallucinogens with receptor models are also addressed in Project 1, and resulting interferences will inform choices of receptor constructs and ligands in protocols of the other Projects. The PPG will thus organize insights from multi-disciplinary experiments into a mechanistic understanding relating h5-HT/2AR actions of hallucinogens to a molecular basis for effects in the whole animal.
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