A suite of engineered mice for interrogating psychedelic drug actions

Psychedelic drugs, such as lysergic acid diethylamide and psilocybin, have emerged as potentially transformative therapeutics for various neuropsychiatric conditions, including depression, anxiety, post-traumatic stress disorder, migraine and cluster headaches. Classical psychedelics exert their effects through activation of 5-hydroxytryptamine 2A receptors (HTR2As). Here we provide a suite of engineered mice that will be useful for clarifying the role of HTR2A in psychedelic drug actions. We generated Htr2a^EGFP-CreERT2 mice to identify both HTR2A-EGFP-CT receptors and HTR2A-containing cells, thereby revealing HTR2A distribution in the brain. We also generated humanized Htr2a^{A242S-EGFP-Cre} and constitutive Htr2a^Cre mice. Psychedelic-induced behavioral changes in these mice validated their utility for these studies. Electrophysiological investigations on brain sections from these mice revealed that 2,5,-dimethoxy-4-iodoamphetamine induced robust increases in firing of genetically identified pyramidal neurons. These mouse lines are valuable tools for investigating the molecular, cellular, pharmacological, physiological, behavioral and other mechanisms of psychedelic actions in vivo.