Acute psilocybin or ethocybin leads to a sustained increase in Pavlovian aversion memory in male mice

There is considerable interest in the concept that psychedelic compounds might facilitate reorganization of emotional processing with therapeutic benefit; in particular, amelioration of excessive focus on past, current and potential-future aversive events, a dominant emotional-cognitive state in stress-related affective disorders. Translational animal models can advance understanding of specific aspects of this concept, namely, those relating to subconscious emotional memories and their neurobiology. In male mice, chronic social stress (CSS) leads to excessive tone/context-foot shock Pavlovian aversion learning (PAL) and memory (PAM), measured as time spent in freezing behavior, and provides a model for generalized excessive focus on aversion. Sub-chronic administration of SSRI antidepressant between PAL and PAM reverses the excessive PAM of CSS mice. Here we applied the model to investigate acute and sustained behavioral and neurobiological effects of psilocybin (PSY) and ethocybin (ETH). In control male mice, both psychedelics at 3 mg/kg per os resulted in 1-2 h of blood-brain exposure to the respective major metabolites psilocin and ethocin, and to head twitch responses. In the main experiment, mice underwent either 15-day CSS or control handling (CON), followed 2 days later by PAL, 1 day later by PSY, ETH or vehicle (VEH), and 3 days later by PAM testing and then brain collection. Relative to VEH, PSY and ETH led to increased PAM expression as more time spent in freezing behavior during tone/context presentation. In a subset of these same mice, there was no psychedelic effect on densities of the two glutamatergic synaptic proteins investigated, vGluT1 or Homer1 in prelimbic cortex or amygdala. This study demonstrates that PSY and ETH lead to a sustained increase in aversive emotional memory expression in male mice. A similar effect in humans with stress- and trauma-related affective disorders might increase the psychotherapeutic accessibility of such memories.