N,N-Dimethyltryptamine effects on fear memory reconsolidation depend on neuronal sigma-1 receptors

Introduction

Post-traumatic stress disorder (PTSD) is characterized by persistent traumatic memories, while current treatments show limited efficacy in targeting them. Modulating reconsolidation may offer a strategy to reduce trauma related fear memory. Ayahuasca, which contains the psychedelic N, N-Dimethyltryptamine (DMT), impairs reconsolidation through neuroplastic-induced mechanisms [1]. Beyond serotonergic receptors, DMT has affinity for the Sigma-1 receptor (S1R), which regulates calcium signaling and microglial reactivity [2]. Whether DMT alone impairs fear memory reconsolidation and the relative contribution of neuronal and microglial S1R contribution to this effect remain unclear.

Aims

To investigate whether DMT impairs fear memory reconsolidation and to determine the respective roles of neuronal and microglial S1R in this effect.

Methods

Adult male and female C57BL/6 mice, Wild Type (WT) and conditional Sigma-1 receptor (S1R) knockout mice, were used. Cell-type-specific S1R deletion was achieved by crossing S1Rfl/fl mice with CX3CR1-CreERT2 mice (“CXCT mice” - microglial deletion, tamoxifen-induced) or NEX-Cre mice (neuronal deletion). Mice were fear conditioned to Context A (5 foot shocks, 0.8 mA/2 s). To induce reconsolidation, mice were re-exposed to Context A (Retrieval) 24 h later; a separate group was exposed to a neutral Context B (No-Retrieval). DMT (1.2 mg/kg) or vehicle was administered i.p. 3 h after Retrieval/No-Retrieval. Fear memory was assessed by freezing time in Context A 1, 8, and 22 days later (Tests A1-A3). Data were analyzed by Student’s t-test or repeated measures ANOVA followed by Newman-Keuls post hoc, with effect sizes estimated by partial eta-square (η²). All procedures were approved by Saarland authorities (license 11/2025).

Results

A significant interaction among Context A exposure × Genotype × Treatment was detected (F3,105 = 4.58, p = 0.005, η² = 0.116). Newman-Keuls post hoc showed that DMT significantly reduced freezing behavior in WT mice in Tests A1-A3, with no effects in neuronal S1R knockout NEX-Cre mice, indicating that neuronal S1R underlies DMT effect on reconsolidation. Of note, this effect lasted up to 22 days, suggesting no spontaneous recovery of fear memory. When memory retrieval was omitted, DMT had no effect on freezing in WT mice (F1,13 = 0.72, p = 0.412, η² = 0.052, N = 7-8/group), confirming that memory reactivation was necessary for DMT’s effect. In microglial S1R knockout CXCT-mice, repeated measures ANOVA showed significant main effects of DMT treatment (F1,35 = 41.83, p < 0.001, η² = 0.544) and genotype (F1,35 = 5.32, p = 0.027, η² = 0.132), with no significant Treatment × Genotype interaction (F1,35 = 0.26, p = 0.614, η² = 0.007), indicating that DMT reduced freezing behavior in a lasting manner regardless of microglial S1R genotype.

Conclusions

DMT disrupts fear memory reconsolidation in a retrieval-dependent manner, an effect that critically depends on neuronal but not microglial S1R. These findings reveal a previously unrecognized role for neuronal S1R signaling in the disruption of persistent fear memories by DMT and provide new mechanistic insight into how psychedelics may be leveraged to develop reconsolidation-based therapeutic strategies for PTSD.

References

1. Daneluz DM, Sohn JMB, Silveira GO, Yonamine M, Stern CA. Evidence on the impairing effects of Ayahuasca on fear memory reconsolidation. Psychopharmacology (Berl). 2022 Oct;239(10):3325-3336. doi: 10.1007/s00213-022-06217-2. Epub 2022 Sep 7. PMID: 36069952.
2. Carbonaro TM, Gatch MB. Neuropharmacology of N,N-dimethyltryptamine. Brain Res Bull. 2016 Sep;126(Pt 1):74-88. doi: 10.1016/j.brainresbull.2016.04.016. Epub 2016 Apr 25. PMID: 27126737; PMCID: PMC5048497.