The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs.

5-MeO-DMT, a natural hallucinogen found in ayahuasca, disrupts brain activity in the medial prefrontal cortex (mPFC) of rodents, increasing firing in 51% and decreasing it in 35% of pyramidal neurons, while reducing the power of low-frequency cortical oscillations (<4 Hz) by 31%. This effect, which depends on 5-HT1A and 5-HT2A receptor activation, resembles disruptions caused by other psychotomimetic agents like phencyclidine and DOI. Antipsychotic drugs (haloperidol, clozapine, risperidone) and an mGlu2/3 agonist reversed the oscillation reduction. 5-MeO-DMT also decreased blood-oxygen level dependent (BOLD) responses in visual cortex and mPFC. The findings suggest these cortical alterations underlie hallucinogenic effects and may aid antipsychotic drug development.

Study at a glance

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (-31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.