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Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.

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The dorsal subiculum (DSub) has reciprocal connections with the dorsal hippocampus, and these regions play a role in spatial representation in contextual fear conditioning (CFC). Recently, we used AP5 and muscimol infusions to show that the DSub is required for CFC consolidation. The CFC component can be present in other learning tasks, such as step-through inhibitory avoidance (ST IA), which requires the dorsal hippocampus for acquisition and consolidation. This suggests that the DSub may be also involved in ST IA if the CFC component of the protocol is strong enough. Therefore, this study tested whether the DSub participates in ST IA acquisition and consolidation in male Wistar rats. Our data showed that pre-or posttraining infusions of AP5 or muscimol into the DSub did not affect ST IA acquisition and consolidation. We discuss the present results in relation to our previous findings, which showed the involvement of the DSub in CFC consolidation, and highlight some reasons that may explain the divergent results between the tasks. First, we note the possibility to escape from the unconditioned stimulus that occurs in ST IA, but not in CFC. We also suggest that the instrumental component of ST IA seems to be more prominent than the CFC one. Finally, we consider the possible influence of aspects of anxiety present in the ST IA, but not in CFC. These possible interpretations provide a broad framework in respect of the present results and raise new questions that demand further studies exploring the DSub function in inhibitory avoidance.

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The psychedelic brew ayahuasca is increasingly being investigated for its therapeutic potential. To review and summarize data available on ayahuasca research using animal models, we systematically searched five databases (PubMed, Web of Science, EMBASE, LILACS and PsycInfo) for peer-reviewed studies in English, Portuguese or Spanish up to July 2022. We identified 32 studies investigating ayahuasca effects on toxicological, behavioural and (neuro)biological parameters in rodents, primates and zebrafish. Toxicological results show ayahuasca is safe at ceremonial-based doses, but toxic at high doses. Behavioural results indicate an antidepressant effect and a potential to reduce the reward effects of ethanol and amphetamine-type drugs, while the anxiety-related outcomes are yet inconclusive; also, ayahuasca can influence locomotor activity, highlighting the importance of controlling for locomotion when analysing tasks depending on it. Neurobiological results show ayahuasca affects brain structures involved in memory, emotion and learning, and that other neuropathways, besides the serotonergic action, are important in modulating its effects. Essential gaps in the ayahuasca field can still be sufficed using animal models.

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