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. 2022 Jan 25;55(3):121–138. doi: 10.1055/a-1721-2914

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The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.

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Fig. 2 — Working hypothesis of psychedelic drug effects on cortico-striato-thalamo-cortical and cortico-cortical circuits of information flow: The schema in Fig. 2 comprises central brain networks on the effects of psychedelic drugs responsible for bottom-up sensory input via the thalamus to the cortex and top-down cortico-striato-thalamic, cortico-thalamic and/or cortico-cortical control of information processing. The model is based mostly on data obtained on the action of LSD and DOI in animals as well as from some studies with LSD and psilocybin in humans. The 5-HT2A receptors are highly expressed in the apical dendrites of layer 5 pyramidal (L5p) neurons in the cortex and are particularly enriched in the prefrontal cortex (PFC) ¹²⁹ ¹³⁰ ¹³¹ . A smaller proportion is located pre-synaptically on thalamocortical afferents projecting to the neocortex ⁹⁶ . 5-HT2ARs are also expressed on GABAergic interneurons in the cortex and subcortical structures ¹³¹ . LSD and DOI both increase extracellular glutamate levels via activation of post-synaptic 5-HT2A receptors on deep layers 5 and 6 pyramidal neurons (L5p) (stage 1) and on Lp6 (stage 2) neurons projecting to L5p neurons ⁹⁶ ¹³² ¹³³ as well as via activation of pre-synaptic 5-HT2A receptors on specific (SP) and non-specific (NSP) thalamocortical afferents ⁹⁶ ¹³⁴ . Psychedelics such as LSD can also stimulate 5-HT1A receptors on the hillock on Lp5 and Lp6 neurons (stage 4) and cortical GABAergic interneurons (stage 5) resulting in both inhibition and disinhibition of prefrontal pyramidal cell activity ¹³² ¹³⁵ ¹³⁶ . Furthermore, LSD or DOI are also potent partial agonists at cortical (stage 6) and subcortical (striatal, pallidal or thalamic) (stage 7) 5-HT2A receptors in GABAergic interneurons ¹³⁷ ¹³⁸ . Despite this partially inhibitory mechanisms, this LSD- or DOI-induced increased glutamate release produces a striking net-excitatory effect on L5p neurons ¹³⁹ ¹⁴⁰ ¹⁴¹ and promotes synaptic plasticity via AMPA and NMDA receptor-dependent mechanisms ⁹⁸ ¹⁰⁵ ¹⁰⁶ ¹³³ ¹⁴² . L5P neurons affect both thalamic and cortical processing and have the unique ability to couple thalamo-cortical (stage 8) and cortico-cortical loops (stage 9) of information streams with each other ¹⁴³ . This is thought to provide a mechanism through which the state and content of consciousness are functionally coupled ¹³⁴ . Psychedelics appear to affect this extended thalamic-cortical broadcasting system and thus consciousness as a whole, by simultaneously producing sensory flooding and arousal via reduced thalamic gating of interoceptive and exteroceptive stimuli and by altering the meaning and attachment of percepts due to disrupted cortico-cortical interactions ¹⁹ ¹⁰⁹ . In this model, thalamic gating is thought to be under the control of glutamatergic cortico-striatothalamic and cortico-thalamic loops projecting back to the cortex, in addition to being under the modulatory influence of serotonergic (and dopaminergic) projections from the raphe (and the VTA) to several parts of the CSTC.