Ayahuasca Impairs Fear Memory Reconsolidation and Promotes Rapid Structural Plasticity in the Hippocampus and Prelimbic Cortex.

Psychedelic drugs promote rapid neuroplasticity in brain regions affected by trauma exposure, such as the prelimbic (PL) cortex and the dorsal hippocampus (DH), being investigated as potential treatments for posttraumatic stress disorder. Ayahuasca (Aya) contains N,N-dimethyltryptamine, a classic psychedelic. Our previous work showed that Aya reduces fear expression by impairing fear memory reconsolidation. We hypothesized that Aya administration during reconsolidation induces neuroplastic changes in DH and PL cortex associated with its behavioral effects. Adult male Wistar rats underwent contextual fear conditioning and received Aya (60 mg/kg, oral gavage) or H₂O (vehicle) 20 min before or 3 h after fear memory retrieval. To confirm the reconsolidation-impairing effect of Aya, animals were re-exposed to the conditioned context 24 h later. Structural plasticity was assessed 24 h after retrieval and drug administration by Golgi-Cox staining of the DH and the PL cortex. Neurogenesis was evaluated 10 days later by doublecortin (DCX) immunohistochemistry of dentate gyrus. Aya significantly reduced freezing behavior, confirming the reconsolidation-impairing effect. This outcome was accompanied by increased dendritic spine density in the CA1, CA3, and dentate gyrus regions of the DH, as well as in the PL cortex. In the PL cortex, Aya altered dendritic branching and length depending on the timing of administration. In contrast, Aya did not affect adult hippocampal neurogenesis. Together, these findings suggest that rapid synaptic remodeling in the DH and PL cortex, rather than changes in adult hippocampal neurogenesis, is associated with the reconsolidation-impairing effect of Aya.