Effects of N, N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression

Abstract

Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to positively affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N, N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague-Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.

Keywords: DMT; N,N-dimethyltryptamine; ayahuasca; depression; post-traumatic stress disorder; psychedelic.

Figure 1.

Principle chemical components of ayahuasca.

Figure 2.

Exploratory behavior and anxiety is impacted by an acute dose of DMT (10 mg/kg). (a) Timeline of behavioral tests. Drug-naïve animals were dosed 1 h prior to the novelty-induced locomotion test. After the completion of that experiment, these same animals were given two days of rest before being administered DMT 1 h prior to the elevated plus maze test. (b–c) Novelty-induced locomotion was quantified as total distance travelled in 1 min bins over time (b) and as the total distance travelled over the entire 45 min experiment (c). (d) The proportion of time spent on the margin of the arena versus the center was determined. (e–f) The number of vertical movements (e) (i.e., rearing) and total time spent rearing (f) were quantified. (g–h) The number of stereotypies (g) and total time spent engaged in stereotypies (h) were quantified. (i–l) Anxiety levels were measured using the elevated plus maze. The percentage of time spent in the open arms (i) as well as the number of open arm entries (j) was quantified. There was no difference between the treatment groups with respect to the total distance moved (k) or average velocity (l). Error bars represent SEM, NS = not significant, *P < 0.05, **P < 0.05 as compared to vehicle control. N = 8 (VEH) N = 9 (DMT). VEH = vehicle, DMT = N,N-dimethyltryptamine

Figure 3.

An acute dose of DMT (10 mg/kg) prior to fear conditioning does not affect contextual or cued fear memory. (a) Experimental design for the fear conditioning experiment. (b) DMT increased immediate freezing following foot shocks, but had no effect on either contextual or cued fear memory. Pre-training and post-training represent the 2 mins immediately before and after the presentation of shocks, respectively. Contextual freezing was determined over the course of the entire 10 min session. Cued freezing was assessed as the percentage of time spent freezing during the 8 tone presentations. Error bars represent SEM, NS = not significant, *P < 0.05 as compared to vehicle control. N = 8 (VEH) N = 8 (DMT). VEH = vehicle, DMT = N,N-dimethyltryptamine

Figure 4.

An acute dose of DMT (10 mg/kg) facilitates cued, but not contextual, fear extinction. (a) Experimental design for the cued fear extinction experiment (N = 16 (VEH) N = 16 (DMT)). Following cued fear conditioning in context A, animals were dosed and subjected to one session of cued extinction training in context B on day 3. On day 4, the DMT-treated group demonstrated significantly lower freezing responses in the absence of drug. (b) Fear conditioning prior to drug treatment demonstrates that there is no difference between the two treatment groups. (c) Cued extinction during training day 3 demonstrates that administration of DMT 1h prior to training does not impair the initial recall of the fear memory, but does enhance within session extinction. (d) Percentage of time spent freezing during each of the 8 auditory presentations on the test day (day 4). (e) Total percentage of time spent freezing during all 8 auditory presentations on the test day (day 4). (f) Experimental design for the context extinction experiment (N = 8 (VEH) N = 8 (DMT)). Animals were fear conditioned in context A, and dosed prior to contextual extinction training (days 3–5). On day 6, contextual fear memory was assessed in the absence of drug. (g) Percentage of time spent freezing during the entire 10 min session on each of the extinction days. Both treatment groups effectively extinguish contextual fear memories over time. The extinction day had a significant effect of freezing levels (P = 0.0073) as analyzed using a repeated measures two-way ANOVA. (h) Individual data points for the contextual extinction test in the absence of drug on day 6. Error bars represent SEM, NS = not significant, *P < 0.05, as compared to vehicle control. VEH = vehicle, DMT = N,N-dimethyltryptamine

Figure 5.

An acute dose of DMT (10 mg/kg) elicits an antidepressant response in the forced swim test similar to ketamine (10 mg/kg). (a) Experimental design of the forced swim test. (b) Quantification of different forced swimming behaviors. Error bars represent SEM, NS = not significant, *P < 0.05, **P < 0.01. N = 6 (VEH) N = 6 (DMT) N = 6 (KET).VEH = vehicle, DMT = N,N-dimethyltryptamine, KET = ketamine