Abstract by Anna Ulstein Odland

Background: Serotonergic psychedelics are one of the most trending topics in neuroscience today. They work by activating the 5-hydroxytryptamine 2A receptor (5-HT_2AR) and have a long use as traditional medicines in some cultures. After a hiatus due to drug prohibition laws and social stigma, researchers can now study psychedelics in modern clinical trials where the compounds show great promise for treating various mental disorders. Psychedelics appear to induce lasting improvements in mental health, and their transdiagnostic therapeutic potential possibly relates to their ability to induce a window of openness and flexibility, where lasting molecular and behavioral changes can occur. The resurgence in psychedelic research comes with an interest in development of new psychedelic medicines, which requires animal studies to drive decision-making in the drug discovery pipeline. The rodent behavioral tests normally used to screen for clinical efficacy of new psychotherapeutics are of questionable utility, since 5-HT_2AR agonist psychedelics show inconsistent effects in such tests, often lack lasting effects, and as the behaviors modeled do not translate to the transdiagnostic potential of psychedelics.

Aim: This project evaluated the effects of serotonergic psychedelics in mouse behavioral tests related to perseveration and cognitive flexibility, with the objective to elucidate the utility of these tests in psychedelic drug discovery.

Methods: We tested the effects of different 5-HT_2AR agonists on mouse perseverative behavior and cognitive flexibility in relevant tests that were set up in our laboratory. This project also included development of a revised reversal learning schedule.

Results: We found that the 5-HT_2AR agonists DOI and 25CN-NBOH acutely reduced perseveration-like repetitive behavior in the marble burying test and improved 8-OH-DPAT-disrupted spontaneous alternation behavior. On the other hand, 25CN-NBOH did not affect reversal learning, which is a test that shares more similarity with human phenomenology. We therefore improved the sensitivity of the reversal learning schedule for detection of serotonergic effects on response inhibition during reversal. The new schedule can be used for future studies, including studies with 5-HT_2AR agonists.

Conclusion: The behavioral tests evaluated in this project were of questionable utility for drug discovery of new psychedelics. The lack of effects on reversal learning behavior in healthy mice does not mirror the increased cognitive flexibility by psychedelics observed in humans. The acute effects of psychedelics on perseverative behavior in the marble burying and spontaneous alternation behavior tests may predict therapeutic efficacy. However, such acute effects do not reflect the lasting therapeutic effects of psychedelics reported in clinical studies, and further investigation into acute versus lasting effects are therefore warranted. This project contributed to mapping of the behavioral pharmacology of psychedelics and highlighted the need for continued research on animal behavioral responses to psychedelics.