N,N-dimethyltryptamine (DMT) is an naturally occurring indoleamine with hallucinogenic and antidepressant effects in humans. Here, we compared the effects of DMT and S-ketamine, a fast-acting antidepressant, in helpless mice. To induce helplessness, male single and group-housed mice were exposed to inescapable footshock stress; only helpless animals were subsequently treated with S-ketamine 10 or 30 mg/kg (ip), DMT 10 or 25 mg/kg (ip), or vehicle and tested in behavioral assays. In depressive-related behavioral tests, S-ketamine and DMT (both at 10 mg/kg), only in group-housed mice, 24 h after administration, reversed escape deficits and reduced escape latency in the learned helplessness model. In helpless single-housed mice, 5 days after drug administration, both compounds (at 10 mg/kg) prevented stress-induced anhedonia in the sucrose preference test. In the tail suspension test, DMT (10 mg/kg) reduced immobility up to 8 days post-injection, whereas the effects of S-ketamine (30 mg/kg) lasted up to 30 h after injection. In anxiety-related behavioral tests, DMT (10 mg/kg), but not S-ketamine, reversed stress-induced hypolocomotion in the open field test, and increased exploration in open arms in the elevated plus-maze up to 5 days post-administration. However, in the novelty-suppressed feeding behavior, at 8 days after drug administration, neither DMT nor S-ketamine altered mouse behavior. Collectively, DMT is as effective as S-ketamine in producing rapid and long-lasting antidepressant effects in helpless mice. Present data also suggest anxiolytic-like effects for DMT. Ultimately, main findings highlight the transdiagnostic therapeutic potential of DMT for stress-related disorders. • S-ketamine evoked fast-acting and long-lasting antidepressant effects in helpless mice; • DMT rapidly and sustainably reversed helplessness and anhedonia in mice; • DMT elicited anxiolytic actions in helpless mice with late onset.
Sousa-Silva et al. (Sun,) studied this question.