The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors

This rodent study (2017) suggests that the hallucinatory effects of 5-MeO-DMT may be due to simultaneous alteration of prefrontal and visual brain activities. The authors point to 5-HT1A receptor antagonists as a potential treatment for visual hallucinations.

Abstract

“5-MeO-DMT is a natural hallucinogen acting as serotonin 5-HT1A/5-HT2A receptor agonist. Its ability to evoke hallucinations could be used to study the neurobiology of psychotic symptoms and to identify new treatment targets. Moreover, recent studies revealed the therapeutic potential of serotonin hallucinogens in treating mood and anxiety disorders. Our previous results in anesthetized animals show that 5-MeO-DMT alters cortical activity via 5-HT1A and 5-HT2A receptors.

Here, we examined 5-MeO-DMT effects on oscillatory activity in prefrontal (PFC) and visual (V1) cortices, and in mediodorsal thalamus (MD) of freely-moving wild-type (WT) and 5-HT2A-R knockout (KO2A) mice. We performed local field potential multi-recordings evaluating the power at different frequency bands and coherence between areas. We also examined the prevention of 5-MeO-DMT effects by the 5-HT1A-R antagonist WAY-100635.

5-MeO-DMT affected oscillatory activity more in cortical than in thalamic areas. More marked effects were observed in delta power in V1 of KO2A mice. 5-MeO-DMT increased beta band coherence between all examined areas. In KO2A mice, WAY100635 prevented most of 5-MeO-DMT effects on oscillatory activity.

The present results indicate that hallucinatory activity of 5-MeO-DMT is likely mediated by simultaneous alteration of prefrontal and visual activities. The prevention of these effects by WAY-100635 in KO2A mice supports the potential usefulness of 5-HT1A receptor antagonists to treat visual hallucinations. 5-MeO-DMT effects on PFC theta activity and cortico-thalamic coherence may be related to its antidepressant activity.”

Authors: Maurizio S. Riga, Laia Lladó-Pelfort, Francesc Artigas & Pau Celada

Summary

5-MeO-DMT, a natural hallucinogen, alters cortical activity via 5-HT1A and 5-HT2A receptors and may be used to treat mood and anxiety disorders.

5-MeO-DMT is a natural serotonergic hallucinogen found in a variety of plant mixtures and in the Sonoran desert toad venom. It is used in ritual ceremonies and for healing and recreational purposes.

Serotonergic hallucinogens are divided into two main classes: indoleamines and phenylalkylamines. The psychotomimetic action of these hallucinogens is at least partially mediated by their agonistic actions at cortical 5-HT2A-R.

Brain electrical activity displays simultaneous rhythms of different frequency, and alterations in cortical oscillatory activity have been associated with psychiatric disorders such as schizophrenia and depression, and have been found in healthy volunteers after the consumption of psychotomimetic agents.

5-MeO-DMT alters the frequency and pattern of discharge of layer V pyramidal neurons in the medial prefrontal cortex (mPFC) and reduces the power of low frequency oscillations in wild-type (WT) and 5-HT2A-R knockout (KO2A) mice, thus pointing to the involvement of 5-HT1A-R in 5-MeO-DMT effects.

Psilocybin has been shown to be effective for treatment-resistant depression, perhaps due to activity changes in the thalamic and PFC areas and to modulation of EEG oscillations.

Previous studies showed that psychotropic agents altered the activity of prefrontal cortex in anesthetized rodents. In the present study, we investigated the actions of 5-MeO-DMT on corticothalamic oscillatory activity in freely moving mice and the potential involvement of 5-HT1A-R using genetic and pharmacological manipulations.

2.1. Animals

The drugs used were 5-MeO-DMT and WAY-100635 maleate, dissolved in saline and injected subcutaneously in the same volume (10 ml/kg).

WT and KO2A mice were treated with saline, 5-MeO-DMT, WAY-100635, and saline. Each mouse was treated randomly once with each pharmacological treatment.

2.3. Electrophysiology: local field potential (LFP) recordings in freely-moving mice

24 mice were implanted with Plastics One electrodes in the medial prefrontal cortex, primary visual cortex, and mediodorsal nucleus of the thalamus under isoflurane anesthesia. Buprenorfine and a prophylactic antibiotic were given during 2e3 consecutive days after surgery.

2.4. Data and statistical analysis

Data were imported to MATLAB environment for off-line power and coherence wavelet analysis, and the areas under curve (AUCs) were calculated for each treatment period. Statistical analysis was performed using Student’s t-tests or three- or two-way ANOVAs followed by post-hoc analysis using Duncan’s test, as appropriate.

3.1. Effect of saline on oscillatory activity in cortico-thalamic networks in WT mice

We compared the effect of saline administration on power spectra and coherences before assessing the effect of 5-MeO-DMT.

WT mice showed a small, yet significant decrease in gamma power and a slight increase in delta, theta and beta powers in V1 and MD post-saline injection.

3.2. Effect of 5-MeO-DMT on oscillatory activity in cortico-thalamic networks in WT mice

In WT mice, 5-MeO-DMT increased theta and gamma bands in mPFC and delta power in V1, and decreased marginally beta power in MD. It also increased mPFC-V1 and mPFC-MD coherence in theta and beta bands.

Comparisons of basal power spectra between genotypes in mPFC, V1 and MD are shown in Table 2. No significant differences were found in theta, beta and gamma bands in V1.

networks in KO2A mice

KO2A mice showed a small decrease in gamma power and a slight increase in delta, theta and beta powers in V1 and MD, compared to WT mice.

3.5. Effect of 5-MeO-DMT on oscillatory activity in cortico-thalamic networks in KO2A mice

In KO2A mice, 5-MeO-DMT increased the power of all examined bands in the mPFC, the V1 and MD, and increased delta power in MD. It also increased inter-regional coherences in the mPFC, V1 and MD.

We carried out a statistical analysis on 5-MeO-DMT effects on power and coherence data in order to assess the effect of genotype, area and band, as well as their interactions. We found that 5-MeO-DMT increased mPFC-MD coherence via activation of 5-HT1A-R in V1 delta band.

3.7. Effects of WAY-100635 on oscillatory activity in corticothalamic networks in KO2A mice

We examined the actions of the 5-HT1A-R antagonist WAY-100635 (WAY) alone on 5-MeO-DMT effects in KO2A mice. WAY increased beta power but did not altercoherence in any band and genotype examined.

5-MeO-DMT induced differential effects on oscillatory activity in WTand KO2A mice. Pretreatment with WAY-100635 prevented 5-MeO-DMT effects on oscillatory activity in all interegion coherences examined, except in delta V1-MD coherence.

4. Discussion

The present results indicate that 5-MeO-DMT alters oscillatory activity in primary visual cortex and cortico-thalamic circuits, and that 5-HT1A-R activation plays a relevant role in the psychotropic action of 5-MeO-DMT. Moreover, 5-MeO-DMT increased theta and gamma bands in mPFC, two key areas implicated in major depression.

KO2A mice have a decrease in delta power, while WT mice have an increase. This is because 5-MeO-DMT has opposite effects when acting on 5-HT1A-R or 5-HT2A-R.

Patients with schizophrenia show alterations in cortical gamma oscillations when performing cognitive tasks, or during resting state, whereas healthy individuals taking 5-MeO-DMT show an increase in cortical gamma power. The preferential 5-HT1A-R agonist 5-MeO-DMT increases gamma power in humans, whereas psilocybin decreases gamma power.

Visual hallucinations are associated with increased basal activity in the visual cortex and aberrant activity within visual thalamo-cortical networks. 5-MeO-DMT altered oscillatory activity on V1 in humans.

5-HT2A-R and 5-HT1A-R are expressed in the visual cortex, and 5-HT2A-R may modulate the excitatory/inhibitory balance, as observed in the mPFC. Moreover, 5-HT2A-R plays a fundamental role in the pathogenesis of visual hallucinations.

KO2A mice showed altered oscillatory activity in theta, beta and gamma bands and decreased theta coherence between mPFC and V1.

In KO2A mice, 5-MeO-DMT alters low band oscillatory activity more markedly than in WT mice, suggesting a preferential action on 5-HT1A-R and/or opposite effects of 5-MeO-DMT acting on 5-HT2A-R and 5-HT1A-R.

Serotonin hallucinogens decrease alpha oscillations and increase cerebral blood flow on visual areas. Moreover, 5-MeO-DMT induces opposite effects on theta and beta bands acting on 5-HT2A-R or 5-HT1A-R.

5-MeO-DMT increased delta band power in MD thalamus, which is consistent with the high density of 5-HT1A-R and 5-HT2A-R in V1 and mPFC and their absence in thalamic nuclei. This increase may be explained by the direct reciprocal V1-PFC and MD-PFC connectivity.

Serotonergic neurotransmission regulates the synchrony between brain areas, and 5-MeO-DMT increases coherence in beta band between all areas examined. 5-HT1A-R and 5-HT2A-R are involved in inter-area synchrony, and WAY100635 avoids 5-MeO-DMT effects on power spectra and coherences except in delta V1-MD coherence.

NMDA-R antagonists such as ketamine and serotonergic hallucinogens such as psilocybin show clinical efficacy in depressed patients resistant to other forms of treatment. Likewise, Ayahuasca, containing dimethyltryptamines in varying proportions, has shown antidepressant efficacy.

Antidepressant treatment and meditation increase frontal theta activity, and 5-MeO-DMT increases PFC-MD coherence. Additionally, deleting GluN2B subunits in MD-PFC synapses may have antidepressant-like effects.

This study shows that 5-MeO-DMT affects oscillatory activity in mouse brain in a manner similar to that seen in human brain.

5. Conclusions

5-MeO-DMT alters population activity in PFC-MD circuits and in V1, with the latter showing the greatest effect size. It also affects synchrony between mPFC and MD, and may be related to its potential antidepressant action.

Conflicts of interest

F.A. and P.C. have received consulting and educational honoraria from Lundbeck and are PI and CoPI of two grants from Lundbeck.