Lysergic Acid Diethylamide Produces Anxiogenic Effects in the Rat Light/Dark Test and Elevated Plus Maze

Summary

LSD treatment in adult male Sprague-Dawley rats showed a dose-dependent decrease in entries and time spent in brightly lit areas during anxiety tests, indicating transient anxiogenic effects. After subchronic LSD administration, rats assessed 48 hours later exhibited significantly more closed arm entries and time spent in closed arms compared to open arms, but this effect was not observed in those tested 72 hours post-injection. These results suggest the need for alternative models to explore the mechanisms behind therapeutic outcomes of psychedelics.

Study at a glance

Abstract

Recent clinical trials indicate favorable therapeutic outcomes of psychedelic-assisted psychotherapy for anxiety and treatment-resistant depression. Whereas the neurobiological systems underlying these effects are not well understood, animal behavioral models can serve to investigate these mechanisms. For the current study, we implemented 2 rodent models predictive of anxiolytic drug effects, a light/dark test and an elevated plus maze (EPM), to investigate the acute and subchronic effects of LSD, respectively. Forty-eight, adult male Sprague-Dawley rats were randomly assigned to receive LSD (0.00, 0.02, 0.04, 0.08 mg/kg) and assessed in the light/dark test 15 min after the first injection. Five additional injections were given, once every 48 hours, after which rats were assessed in the EPM either 48 (n = 24) or 72 hours (n = 24) after the last injection. A dose-dependent and statistically significant decrease was observed in number of entries into, F(3, 44) = 12.79, p < .001,η2 = .47, and time spent, F(3, 48) = 14.15, p < .001, ηp2 = .47, in the brightly lit compartment. In the EPM, closed arm entries, F(1, 17) = 28.85, p < .001, ηp2 =.36, and time spent in closed arms, F(1, 17) = 20.14, p < .001, ηp2=.99, were significantly higher compared to entries or time in open arms by rats assessed 48 hours after the last LSD injection, but not by rats tested 72 hours after the last injection. These findings indicate that acute and subchronic LSD treatment produce transient anxiogenic effects. In consideration of positive therapeutic outcomes of psychedelic-assisted psychotherapy, alternative preclinical models may be warranted to discern the mechanisms underlying the putative therapeutic effects of serotonergic hallucinogens.