Psychedelic-Induced Serotonin 2A Receptor Downregulation Does Not Predict Swim Stress Coping in Mice

Abstract

Serotoninergic psychedelics such as psilocybin have been reported to elicit a long-lasting reduction in depressive symptoms. Although the main target for serotoninergic psychedelics, serotonin type 2A receptor (5-HT_2A), has been established, the possible mechanism of the antidepressant action of psychedelics remains unknown. Using the mouse forced swim test model, we examined whether the administration of the synthetic serotoninergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) would modulate 5-HT_2A receptor levels in the medial prefrontal cortex (mPFC) and revert stress-induced changes in behavior. Mice subjected to swim stress developed a passive stress-coping strategy when tested in the forced swim test 6 days later. This change in behavior was not associated with the hypothesized increase in 5-HT_2A receptor-dependent head twitch behaviors or consistent changes in 5-HT_2A receptor levels in the mPFC. When DOI was administered 1 day before the forced swim test, a low dose (0.2 mg/kg i.p.) unexpectedly increased immobility while a high dose (2 mg/kg i.p.) had no significant effect on immobility. Nevertheless, DOI evoked a dose-dependent decrease in 5-HT_2A levels in the mPFC of mice previously exposed to swim stress. Our findings do not support the hypothesis that the downregulation of 5-HT_2A receptors in the mPFC contributes to the antidepressant-like properties of serotoninergic psychedelics.

Keywords: 5-HT2A; DOI; behavioral despair; downregulation; head twitch; mPFC; mice; psychedelics; stress.

Figure 1

Effect of swim-stress exposure on 5-HT_2A receptor-mediated behavior in mice. (A) Experimental design. Mice were exposed to 15 min forced swim stress or stayed in a home cage on day 0. On day 6, mice received a single injection of a vehicle solution (1% DMSO in saline, Con: n = 16, Str: n = 12) or DOI (low dose: 0.2 mg/kg, Con: n = 16, Str: n = 10; high dose: 2.0 mg/kg, Con: n = 16, Str: n = 10). Behavior of mice was immediately recorded for locomotor activity and head twitch assessment. (B) Total head twitch count observed for 15 min after treatment. Head twitch scores for the vehicle groups were obtained and plotted for a limited number of mice and used as a visual reference. (C) Activity measured by distance traveled. Data are represented as mean values +/− SEM.

Figure 2

Effect of DOI on passive stress-coping behavior in the forced swim test in mice. (A) Latency to immobility. (B) Immobility count. (C) Climbing behavior. (D) Swimming behavior. Plots represent classification of 5 s intervals. Data are represented as mean values +/− SEM. * p < 0.05 vs. Veh group.

Figure 3

Effects of DOI administration on 5-HT_2A/PSD-95 ratio in a crude membrane fraction of the mouse mPFC. (A) Representation of a target area. (B) Representative western blot results for the 5-HT_2A receptor and PSD-95 signal. (C) Quantification of 5-HT_2A/PSD-95 signal ratio, normalized to control vehicle group. Data are represented as mean values +/− SEM. * p < 0.05 vs. Veh group.