THE ROLE OF THE ENVIRONMENTAL CONTEXT IN THE NEUROPLASTICITY-INDUCED THERAPEUTIC EFFECTS OF PSYCHEDELICS

Psychedelics promote neuroplasticity through directly binding to TrkB and potentiating BDNF binding, and this has been shown to be the root of their therapeutic effects. However, increased neuroplasticity may not be necessarily beneficial, and environmental factors could play a role in their therapeutic outcome.
In humans, a “bad trip” during the acute effects of psychedelics can lead to long-lasting untoward effects. We induced a bad trip in mice by exposing them to a Fear Conditioning paradigm during the acute effects of LSD and monitored the long-term fear response, as well as depressive-like symptoms using the IntelliCage system. Our bad trip model showed that, despite the aversive experience during the acute effects, LSD still promoted fear erasure and prevented the bad trip-induced anhedonic and anxiogenic-like behavior.
To explore the environmental modulation of LSD-induced neuroplasticity on mouse behavior, we exposed mice to an unpredictable chronic-mild stress paradigm within IntelliCages. Mice were then exposed to LSD and either continued in a stressful environment or were placed in an enriched environment for an additional 2 weeks and were monitored for depressive-like behavior. The unpredictable chronic-mild stress induced a depression-like phenotype, and LSD treatment showed a tendency towards amplifying the environment and to promote anhedonic behavior.
In conclusion, our results support the role of environmental context during the LSD-induced increase in plasticity to overcome the detrimental effects of a bad trip experience in the long-term, and the potential for LSD-induced plasticity to exacerbate the effects of continued aversive environment to produce an adverse outcome.