5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines

Abstract

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns and limit their clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding of how these molecules produce therapeutic effects. While the hallucinogenic properties of psychedelics are generally attributed to activation of serotonin 2A receptors (5-HT2ARs), it is currently unclear if these receptors also mediate their antidepressant effects as several nonhallucinogenic analogues of psychedelics with antidepressant-like properties have been developed. Moreover, many psychedelics exhibit promiscuous pharmacology, making it challenging to identify their primary therapeutic target(s). Here, we use a combination of pharmacological and genetic tools to demonstrate that activation of 5-HT2A receptors is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. Our results suggest that psychedelic tryptamines can induce hallucinogenic and therapeutic effects through activation of the same receptor.

Keywords: 5-HT2A receptor; 5-methoxy-N,N-dimethyltryptamine; Psychedelic; depression; neuroplasticity; psilocybin; psychoplastogen; structural plasticity.

Figure. 1.. 5-MeO promotes cortical spine growth.

(A) Schematic depicting the experimental design for spinogenesis studies. (B) Rat embryonic cortical cultures were treated on DIV21 with compounds (10 μM), and dendritic spine density was assessed 24 h later. Representative images are shown. (C) Quantification of dendritic spine density demonstrated that both 5-MeO and KET increased spine density compared to the VEH control. (D) The effect of 5-MeO (1 μM) on spinogenesis was blocked by ketanserin (10 μM, 15 min pretreatment). VEH = vehicle; KET = ketamine; 5-MeO = 5-methoxy-N,N-dimethyltryptamine, KETSN = ketanserin; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, as compared to VEH controls, one-way ANOVA with Dunnett’s post hoc test.

Figure. 2.. 5-MeO produces an antidepressant-like effect through activation of 5-HT2 receptors.

(A) Schematic of the FST design. (B–D) Male mice were administered VEH or KETSN (4 mg/kg, IP) 10 min prior to administration of 5-MeO (10 mg/kg, IP). Ketanserin completely blocked the HTR induced by 5-MeO (B), but did not block 5-MeO-induced hypolocomotion (C and D). (E) A pretest demonstrated that immobility in the FST was the same for all groups prior to compound administration. (F) Pretreatment with KETSN (4 mg/kg, IP) blocks the antidepressant-like effect of 5-MeO-DMT (10 mg/kg, IP) in the FST. 5-MeO = 5-methoxy-N,N-dimethyltryptamine; VEH = vehicle, KETSN = ketanserin. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, as compared to VEH – KETSN controls, one-way ANOVA with Dunnett’s post hoc test.

Figure 3.. Intrinsic excitability is not impacted by a single administration of 5-MeO.

(A) Layer 5 mPFC pyramidal neurons from animals administered a single dose of 5-MeO (10 mg/kg, IP) 24 h prior to tissue collection showed no significant difference in action potential firing rates in response to depolarizing current injection (n = 75 neurons, 6 animals per group) compared to neurons from animals that were given saline (n = 87 neurons, 6 animals per group). (B) Sample traces of neurons from animals treated with vehicle (black) and 5-MeO (red) in response to +200, +100, 0, −100, and −200 pA current injections (scale bars: 200 ms, 20 mV). (C) Resting membrane potential (RMP) was significantly more depolarized in animals treated with 5-MeO (p = 0.020), but all other intrinsic cellular properties were largely unchanged by the drug treatment. Data represent mean ± SEM. *p < 0.05, Student’s t-test.

Figure 4.. 5-MeO produces sustained, but not rapid, antidepressant-like effects in the FST.

(A) Schematic depicting the experimental design for FST studies. A pre-test was performed on Day 1. On Day 2, compounds were administered to male and female mice (5-MeO, 10 mg/kg, IP; KET, 3 mg/kg, IP) and a FST was performed 30 mins later. The animals were returned to their home cages for 1 week before another FST was performed. (B) The treatment groups did not exhibit any differences during the pre-test. Ketamine produced a rapid antidepressant-like effect within 30 mins of administration, and both ketamine and 5-MeO decreased immobility 7 days after treatment. VEH = vehicle; KET = ketamine; 5-MeO = 5-methoxy-N,N-dimethyltryptamine. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, as compared to VEH controls, one-way ANOVA with Dunnett’s post hoc test.

Figure 5.. Psilocybin rescues CORT-induced anhedonia through activation of 5-HT2ARs.

(A) Schematic depicting the experimental design. A SPT was performed on Day 1 followed by 10 days of chronic CORT administration. A second SPT was performed on Day 12 prior to administration of VEH or PSY (10 mg/kg, IP) on Day 13. On day 14, a third SPT was performed. (B) Chronic administration of CORT induced anhedonia in both WT and 5-HT2AR KO mice. (C) A single administration of PSY rescued CORT-induced anhedonia in WT, but not 5-HT2AR KO mice. Administration of VEH had no effect in either genotype. VEH = vehicle; PSY = psilocybin; WT = wild type. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, Student’s t-test (paired).