Efeitos farmacológicos dos principais compostos ativos da ayahuasca sobre comportamentos do tipo ansioso e memória no peixe paulistinha (Danio rerio)

Abstract

Anxiety disorders are among the most prevalent mental health ailments affecting millions of people around the world. Despite substantial progress in the development of new drugs to treat anxiety disorders, current treatments have limited efficacy. Thus, an enormous effort has been devoted to the search for alternative pharmacological treatments. A class of drugs with a pivotal serotonergic agonist action known as psychedelics have shown to be a promising treatment alternative for anxiety disorders, and for the cognitive deficits exhibited by critically depressed patients with co-morbid anxiety. One particular psychedelic, known as Ayahuasca, that is made from the combined infusion of Banisteriopsis caapi stem rich in monoamine oxidase inhibitors (MAOi) such as Harmine and other Beta-Carbolines, and Psychotria viridis leaves, rich in N, Ndimethyltryptamine (DMT), has particularly stood out as a new treatment for depression and anxiety disorders. For the purposes of this study, we evaluated the effects of increasing concentrations of the main active compounds found in Ayahuasca on the behavioral performance of zebrafish (Danio rerio). Adult zebrafish were exposed to 3 different concentrations of: DMT, Harmine, and both alkaloids combined. To determine the therapeutic effects of the alkaloids on memory, and anxiety, behavioral parameters of the zebrafish were assessed with a Novel Tank Diving task and a Conditioned Place Aversion (CPA) task in which place-conditioned aversive memory of the zebrafish was assessed, alongside locomotive behavioral parameters indicative of anxious type behaviors. The behavioral variables analyzed for this study were average swimming speed, maximum speed, total distance covered, freezing, number of entries in the checkered pattern of the CPA tank associated with an aversive stimulus (alarm substance), and time spent on each side of the CPA tank. The results of this study showed that chronic treatment (10 exposures, with a 3-day interval) with increasing concentrations of the main active compounds of Ayahuasca (either independently administered or together) exerted 8 pharmacological anxiolytic effects in conditioned place aversion and the novel tank task. For parameters related to anxiety in both tasks, high concentrations of harmine, and DMT in association with harmine were effective while DMT in all concentrations was only effective in the CPA task. In regards to the effects of these compounds on place-conditioned aversion, we observed that only the low DMT concentration of 0.0038 mg/L significantly made fish spend more time in the side of the CPA tank that was not associated with an aversive stimulus (alarm substance). With this low concentration, animals also exhibited an anxiolytic effect on the CPA task aside from the effect observed on the time that was spent on each side of the CPA tank. These results suggest that low concentrations of DMT might influence the time spent on each side of a CPA tank during testing, while any concentration of DMT and higher concentrations of harmine have anxiolytic properties