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-HT2A 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 hallucinogenesis also remains obscure. To eliminate these important gaps in knowledge and understanding , this Program Project Grant (PPG) addresses a continuum of interrelated questionsabout function and effects elicited by hallucinogens on various mutant constructs of the human 5- HT2A 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 three component Projects: Structure-related investigations link experimental approaches in Project 2 with comprehensive computational 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 mcie. All three Projects will take advantage of the same mutant h5-HT2AR constructs designed and characterized in Project 1&2 collaborations on the basis of specific structural hypothesis. Examples include one that equalizes the efficacies of 5-HT and hallucinogens (e.g., LSD), one that exhibits agonist-independent stimulation of second messenger production. Structure-activity considerations for distinctive modes of interaction of hallucinogens with receptor models are also addressed in Projects 1, and resulting inferences will inform choices of receptor constructs and ligands in protocols of the other Projects. The PPG will thus organize insights from multidisciplinary experiments into a mechanistic understanding relating h-5HT2AR actions of hallucinogens to a molecular basis for effects in the whole animal.
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