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Models of psychedelic drug action: modulation of cortical-subcortical circuits - PubMed

  • ️Sat Jan 01 2022

Models of psychedelic drug action: modulation of cortical-subcortical circuits

Manoj K Doss et al. Brain. 2022.

Abstract

Classic psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have recaptured the imagination of both science and popular culture, and may have efficacy in treating a wide range of psychiatric disorders. Human and animal studies of psychedelic drug action in the brain have demonstrated the involvement of the serotonin 2A (5-HT2A) receptor and the cerebral cortex in acute psychedelic drug action, but different models have evolved to try to explain the impact of 5-HT2A activation on neural systems. Two prominent models of psychedelic drug action (the cortico-striatal thalamo-cortical, or CSTC, model and relaxed beliefs under psychedelics, or REBUS, model) have emphasized the role of different subcortical structures as crucial in mediating psychedelic drug effects. We describe these models and discuss gaps in knowledge, inconsistencies in the literature and extensions of both models. We then introduce a third circuit-level model involving the claustrum, a thin strip of grey matter between the insula and the external capsule that densely expresses 5-HT2A receptors (the cortico-claustro-cortical, or CCC, model). In this model, we propose that the claustrum entrains canonical cortical network states, and that psychedelic drugs disrupt 5-HT2A-mediated network coupling between the claustrum and the cortex, leading to attenuation of canonical cortical networks during psychedelic drug effects. Together, these three models may explain many phenomena of the psychedelic experience, and using this framework, future research may help to delineate the functional specificity of each circuit to the action of both serotonergic and non-serotonergic hallucinogens.

Keywords: circuit models; claustrum; default mode network; psilocybin; thalamus.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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Figures

Figure 1
Figure 1

Summary of the cortico-thalamo-cortical and CSTC loops. Disruption of this circuit by 5-HT2A activation is hypothesized to inundate the cortex with sensory information, contributing to the alterations of cognition and perception during psychedelic experiences. Glu = glutamate; TRN = thalamic reticular nucleus.

Figure 2
Figure 2

Summary of the hippocampal-cortical processing loop implicated in the REBUS model. Psychedelic action is hypothesized to preferentially enhance bottom-up prediction error signalling to higher-level structures compared with top-down reciprocal signalling. This manifests as decreases in cortical synchrony in addition to relaxed priors. The REBUS model specifies hippocampus and the parahippocampal gyrus as originators of this bottom-up signalling, in concert with other unspecified structures. Glu = glutamate.

Figure 3
Figure 3

Summary of the CCC model circuitry. In this model, disruption of prefronto-claustro-cortical circuitry by 5-HT2A activation dysregulates cortical network initiation, which contributes to the disruption of cortical network states (yellow circles). Turquoise and yellow circles depict two network states that arise from the dynamic synchronization of cortical regions across time. The first (turquoise circles) is a network state in which frontal, associative and sensory cortices are synchronized (represented by a similar wave form in each of the turquoise circles), and the second (yellow circles) is a state in which the network is disrupted across various cortical regions (represented by different waveforms in each of the yellow circles). Glu = glutamate.

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