Psychedelics promote structural and functional neural plasticity

This cell (in vitro) and animal (in vivo, larvae & rats) study shows the various ways (stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways) through which psychedelics promote/increase plasticity in the brain.

Abstract

“Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.”

Authors: Calvin Ly, Alexandra C. Greb, Lindsay P. Cameron, Jonathan M. Wong, Eden V. Barragan, Paige C. Wilson, Kyle F. Burbach, Sina Soltanzadeh Zarandi, Alexander Sood, Michael R. Paddy, Whitney C. Duim, Megan Y. Dennis, A. Kimberley McAllister, Kassandra M. Ori-McKenney, John A. Gray & David E. Olson

Notes

This paper is included in our ‘Top 12 Articles on Psychedelics and Serotonin (5HT) Receptors‘

Summary

SUMMARY

Psychedelics, like ketamine, can promote neuritogenesis and/or spinogenesis in the prefrontal cortex. These changes are accompanied by increased synapse number and function, which could explain the clinical effectiveness of these compounds.

Ly et al. demonstrate that psychedelic compounds increase dendritic arbor complexity, promote dendritic spine growth, and stimulate synapse formation.

INTRODUCTION

Neuropsychiatric diseases, including depression and anxiety disorders, place an enormous economic burden on society and share common neural circuitry.

Stress and depression can cause structural and functional changes in the prefrontal cortex (PFC), which can be counteracted by compounds capable of promoting plasticity in the PFC. However, only a relatively small number of compounds have been identified so far, each with significant drawbacks.

Ketamine has shown remarkable clinical potential as an antidepressant and for treating PTSD and heroin addiction. Its therapeutic effects may stem from its ability to promote dendritic spine growth.

Serotonergic psychedelics and entactogens have been shown to have rapid and long-lasting antidepressant and anxiolytic effects in the clinic after a single dose, including in treatment-resistant populations. However, the mechanism of action of these drugs remains poorly understood, and concerns about safety have severely limited their clinical usefulness.

We report that serotonergic psychedelics and entactogens from a variety of chemical classes promote structural and functional neural plasticity in cortical neurons, and that these compounds may have value as fast-acting antidepressants and anxiolytics with efficacy in treatment-resistant populations.

Psychedelics Promote Neuritogenesis

We treated cultured cortical neurons with psychedelics and measured the resulting changes in various morphological features. We found that psychedelics increased dendritic arbor complexity comparably to ketamine, and had a limited effect on the number of primary dendrites.

Psychedelic compounds increase dendritic arbor complexity by promoting neuritogenesis. This effect is limited to select compounds, because serotonin and D-amphetamine exert minimal to no effects on neuritogenesis.

We conducted 8-point dose-response studies to establish the relative potencies and efficacies of hallucinogens and entactogens for promoting neurite outgrowth. We found that LSD was the most potent psychedelic and entactogen, exhibiting activity across 8 orders of magnitude into the low picomolar range.

The anti-addictive alkaloid ibogaine had no effect, which was surprising because we hypothesized that its long-lasting anti-addictive properties might result from its psychoplastogenic properties. However, noribogaine increased dendritic arbor complexity with an EC50 value comparable to ketamine.

We treated Drosophila larvae with LSD and DOI to assess the in vivo effects of classical psychedelics on neuritogenesis. We did not observe any differences in head sizes or activity levels between the treatment groups. We treated Drosophila larvae with psychedelics during the late second instar and found that the compound increased the branching of class I neurons, suggesting that psychedelics act through an evolutionarily conserved mechanism.

Psychedelics Promote Spinogenesis and Synaptogenesis

We treated mature rat cortical cultures with DOI, DMT, and LSD to assess the effects of psychedelics on spinogenesis. All three compounds increased the number of dendritic spines per unit length and shifted spine morphology toward immature over mature spine types.

We administered a 10 mg/kg dose of DMT intraperitoneally to rats to assess the effects of DMT on spinogenesis in the PFC. The results showed that DMT produced positive effects in behavioral tests relevant to depression and PTSD. We wanted to directly compare the effects of DMT with ketamine, and we found that the density of dendritic spines on cortical pyramidal neurons was increased 24 hr after dosing with DMT, and this increase was accompanied by functional effects.

Because DMT has a short half-life (15 min), these results confirm that structural and functional changes induced by DMT persist for hours after the compound has been cleared from the body. Moreover, these changes mirror those produced by ketamine in the PFC.

Psychedelics Promote Plasticity through a TrkB-and mTOR-Dependent Mechanism

Psychedelics can increase levels of BDNF, which is involved in both neuritogenesis and spinogenesis. When cortical cultures were treated with a selective antagonist of BDNF’s high-affinity receptor TrkB, the ability of psychedelics or BDNF to stimulate neuritogenesis and spinogenesis was completely blocked.

TrkB activation promotes signaling through mTOR, which plays a role in structural plasticity, synaptogenesis, and the effects of ketamine.

The 5-HT2A Receptor Mediates the Effects of Psychedelics on Structural Plasticity

We sought to determine whether the 5-HT2A receptor played any role in the plasticity-promoting effects of DOI, DMT, and LSD. We found that ketanserin, a selective 5-HT2A antagonist, completely abrogated the ability of DMT, LSD, and DOI to promote both neuritogenesis and spinogenesis.

We used doses of psychoplastogens that produced maximal effects on structural plasticity in combination with a 10-fold excess of ketanserin. Ketanserin blocked the psychoplastogenic effects of LSD by 50% when treated at 10 nM, and completely prevented LSD-induced neuritogenesis at 100 nM.

Most psychoplastogens had concentration responses that deviated from 1.0, implying polypharmacology. DMT was the only one to exhibit a concentration response greater than 1.0, indicating cooperativity.

DISCUSSION

Classical serotonergic psychedelics cause changes in mood and brain function that persist long after the acute effects of the drugs have subsided. Moreover, psychedelics elevate glutamate levels in the cortex and increase gene expression of the neurotrophin BDNF.

Two reports suggested that psychedelics might be able to produce changes in neuronal structure. We demonstrate that psychedelics from the ergo-line, tryptamine, and iboga classes of compounds can also promote structural plasticity.

This work identified several psychoplastogens, including ketamine, GLYX-13, LY341495, 7,8-DHF, and scopolamine. Several of these compounds were more efficacious or more potent than ketamine, providing additional lead scaffolds for medicinal chemistry efforts aimed at identifying neurotherapeutics.

Psychedelics induce plasticity in cortical cultures, and this plasticity is also observed in vivo using vertebrate and invertebrate models. This suggests that in vitro assays using cortical cultures may have value for identifying psychoplastogens and fast-acting antidepressants.

Psychedelics increase the density of dendritic spines on cortical neurons, and this increase is accompanied by functional effects such as increased amplitude and frequency of spontaneous EPSCs. These effects are similar to those of ketamine, which promotes fear extinction learning and has antidepressant effects in the forced swim test.

Ketamine and psychedelics stimulate mTOR in the PFC, and this stimulation causes similar downstream effects on structural plasticity. Non-hallucinogenic analogs of psychedelics could be critical to resolving the long-standing debate in the field concerning whether the subjective effects of psychedelics are necessary for their therapeutic effects.

Our data demonstrate that psychedelics promote growth of neurites and dendritic spines in vitro, in vivo, and across species, suggesting that these molecules may be used as lead structures to identify next-generation neurotherapeutics with improved efficacy and safety profiles.

In vitro studies were conducted using DMSO and diluted 1:1,000. In vivo studies were conducted using DMT or ketamine dissolved in saline and administered intraperitoneally at a dose of 10 mg/kg.

Sprague-Dawley rats were used in the experiments. The experiments were approved by the IACUC and the University of California, Davis has an Animal Welfare Assurance number on file with OLAW.

Primary cortical cultures were prepared using tissue from embryonic day 18 (E18) Sprague-Dawley rats. The cultures were maintained in a medium containing 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-streptomycin, and 0.5 mM glutamine, and were replicated on at least two occasions by two or more experimenters.

Statistical Analysis

Statistical analyses were performed using GraphPad Prism (version 7.0a). A one-way analysis of variance was performed for comparisons of three or more groups, and a Kolmogorov-Smirnov test was used to compare probability distributions.