IDENTIFYING THE NEUROPHYSIOLOGICAL MECHANISMS UNDERLYING THE POTENTIAL THERAPEUTIC EFFECTS OF PSYCHEDELIC COMPOUNDS

Psychedelics are seeing renewed interest due to their potential as therapeutic tools; however, despite promising clinical findings, the underlying signaling mechanisms and brain-region specific effects of psychedelics remain unclear. This dissertation first describes a comprehensive study aimed at understanding the on and off-target actions of ~40 diverse psychedelic substances representing each class of psychedelic compounds: the tryptamine, phenethylamine, and lysergamide groups. Significant serotonergic, dopaminergic, and adrenergic agonism activities are described, but all tested psychedelic compounds are found to be agonists at the 5-HT2A serotonin receptor. This dissertation next describes the effects of the seven most common naturally occurring sequence variations in the human 5-HT2AR gene on the signaling of four commonly used psychedelic drugs. The 5-HT2AR is robustly enriched in layer V pyramidal (L5p) neurons in both rodent and human cortices, and positron emission tomography studies in humans have shown that psilocin’s psychedelic effects correlate with 5-HT2AR occupancy in the prefrontal cortex (PFC)[1]. As part of this dissertation, electrophysiological studies identify a population of 5-HT2AR neurons in the prelimbic (PrL)/anterior cingulate (ACC) region of the PFC. Psilocin and the 5-HT2AR-prefering compound 25-CN-NBOH increased firing in these neurons through a mechanism that is both 5-HT2AR and Gq dependent. Finally, in contrast, the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) reduces firing in both 5-HT2AR neurons and non-5-HT2AR neurons in a non-5-HT2AR dependent manner. Together, these data provide robust insights into psychedelic drug action by examining the receptor pharmacology of psychedelic compounds, the impact of genetic variance on 5-HT2AR signaling, the neurophysiological effects of psychedelics in the PFC, and the differential effects of a non-hallucinogenic LSD analog on PFC cellular physiology and behavior.