Single ayahuasca administration mitigates long-term behavioral and neurochemical effects of early-life stress in rats

Abstract Pharmacotherapy for depression is commonly prescribed, yet fewer than half of patients achieve remission with a single treatment. Many also experience intolerable side effects, highlighting the need for new treatment approaches. Classic psychedelics interact with the serotonin (5-HT) receptor class and are therefore strongly involved in the treatment of psychiatric illnesses such as depression, anxiety, and substance abuse, demonstrating great therapeutic potential. Specifically, Ayahuasca (AYA) is primarily used for physical or spiritual healing, and the effects resulting from its use are related to its serotonergic activation. Thus, the present study aimed to evaluate the behavioral and neurochemical effects of ayahuasca treatment in Wistar rats subjected to an animal model of depression induced by maternal deprivation (MD). To induce depressive-like behavior, MD was performed on the pups for 3 h/day for 10 days (1st to 10th day of life). Subsequently, rats underwent behavioral testing to assess anxiety- and depressive-like behavior using the elevated plus maze, open field test, splash test, and forced swim test. The levels of dopamine (DA), serotonin (5-HT), brain-derived neurotrophic factor (BDNF), antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities, and oxidative stress biomarkers were assessed in the frontal cortex, hippocampus, and striatum 15 days after ayahuasca administration. MD promoted increased anxiety-like and depressive-like behaviors. Also, anxiety-like and depressive-like behaviors, as well as decreased BDNF and monoamine levels and increased oxidative stress induced by this model, were attenuated by treatment with a single dose of AYA, demonstrating significant therapeutic potential. The findings highlight the need for translational research of new pharmacological approaches for MDD.