Mechanistic insights into LSD actions at 5-HT2A serotonin receptors

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Psychedelic drugs continue to be used and abused by large numbers of individuals within the US and recently there has been a resurgence of interest in the actions of psychedelic drugs like lysergic acid diethylamide (LSD). It is currently unknown how LSD and related psychedelic drugs exert their actions at the molecular and atomic levels. In this MERIT extension we will elucidate the molecular mechanisms by which LSD and related drugs interact with multiple G protein coupled receptors. We will also determine the potential relevance of differences between human and rodent receptors for the actions of LSD and related drugs in vitro and in vivo. Finally we will examine the effects of LSD and related drugs on the gene transcriptional changes which occur specifically in neurons which express receptor essential for the actions of LSD. Taken together, these new findings will provide molecular and atomic details regading the actions of psychedelic drugs in vitro and in vivo. RELEVANCE (See instructions): In this grant we will illuminate the molecular details responsible for LSD's actions at the molecular level. We will combine structural studies of psychedelic receptors complexed with LSD and related drugs. We will also interrogate the role of specific differences between rodent and human receptors as well as transcriptional changes downstream of psychedelic drug actions.