Drugs of abuse with an apparently unique mechanism of action producing disturbances in thought, perception andmood. The mechanisms for these actions of hallucinogens are unknown, but their association with 5-HT2A receptoractivities is longstanding. Despite considerable progress in characterizing behavioral, physiological, andpharmacological properties of serotonergic hallucinogens, the molecular signature underlying the hallucinogenicpotential remains elusive. The exact role of the 5-HT2A hallucinogenesis also remains obscure. To eliminate theseimportant gaps in knowledge and understanding , this Program Project Grant (PPG) addresses a continuum ofinterrelated 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 3Dreceptor models and ligand structures. The fundamental molecular level of understanding sought here for themechanisms of action of hallucinogens also aims to enable future efforts in structure-based design of therapeuticmodalities against their abuse. The PPG is organized around three component Projects: Structure-relatedinvestigations link experimental approaches in Project 2 with comprehensive computational modeling, dynamicssimulation, and structure analysis and design in Project 1. Functional probing for distinct mechanisms in the effects ofhallucinogens on signal transduction, gene expression and behavior will be carried out in Projects 2&3 withpharmacological, biochemical and behavioral approaches involving genetically modified constructs in cell systems andwhole mcie. All three Projects will take advantage of the same mutant h5-HT2AR constructs designed andcharacterized in Project 1&2 collaborations on the basis of specific structural hypothesis. Examples include one thatequalizes the efficacies of 5-HT and hallucinogens (e.g., LSD), one that exhibits agonist-independent stimulation ofsecond messenger production. Structure-activity considerations for distinctive modes of interaction of hallucinogenswith receptor models are also addressed in Projects 1, and resulting inferences will inform choices of receptorconstructs and ligands in protocols of the other Projects. The PPG will thus organize insights from multidisciplinaryexperiments into a mechanistic understanding relating h-5HT2AR actions of hallucinogens to a molecular basis for effects in the whole animal.
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