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Psychedelic Information Theory

Shamanism in the Age of Reason

Psychedelic Information Theory : Chapter 07

5-HT2A Agonism and Multisensory Binding

Most visual hallucinogens are active as full or partial agonists at the 5-HT2A receptor subtype, and all produce similar visual hallucinations that are immediately recognizable as psychedelic.1 Although the 5-HT2A receptor subtype is not the only receptor implicated in hallucinogenesis,2 it is one of the most studied hallucinogenic targets and offers some insights into the quality of classical psychedelic interaction. 5-HT2A receptors are ubiquitous throughout the nervous system, found in the sensory cortex, the frontal cortex, the olfactory cortex, the basal ganglia, the cerebellum, the hippocampus, thalamic nuclei, brainstem nuclei, sensory neurons, platelets, fibroblasts, intestines, smooth muscles, and cardiovascular systems.3,4,5,6 By following the pathways of 5-HT2A modulated signal transduction through the human organism it is possible to extrapolate that psychedelic experience is not limited to mere hallucination, but is instead a complex multi-layered experience integrated throughout all biological signaling systems. The layering of cellular signaling systems mediated by 5-HT provides a framework for viewing the 5-HT2A pathway as a primary modulator for homeostatic feedback regulation of multisensory awareness, behavior, and learning.7 5-HT2A receptor agonists (hallucinogens) promote disinhibition and excitability in 5-HT mediated pathways, indicating that psychedelic action is the product of spontaneous nonlinear feedback excitation in the recurrent circuits responsible for real-time binding of sensation to multisensory perception, affective behavior, and the process of consciousness.

5-HT2A receptor mechanics

The 5-HT2A receptor is a G protein-coupled receptor (GPCR), which means it does not activate ion channels or directly alter cell polarity, but instead sets off a chain reaction of intracellular signaling systems involving phosphatidylinositol (PI) hydrolysis, the production of inositol trisphosphate (IP3), the release of calcium (Ca2+), and the activation of protein kinase C (PKC) and various mitogen-activated protein kinases (MAPK).6,8,9,25 PKC regulates a variety of cellular functions at the membrane, including signal transduction, receptor desensitization, and synaptic formation and strengthening responsible for learning and memory.10 MAPK regulates fundamental intracellular functions such as gene expression, proliferation, cell growth, and survival.26 It is interesting to note that Salvinorin A, another potent hallucinogen not active at the 5-HT receptor, also stimulates PKC and MAPK signaling pathways via Kappa Opioid receptors.28,29,30 These receptor-mediated secondary pathways undoubtedly play a role in psychedelic neuroplasticity and cellular regeneration,27 but these secondary messengers are not necessarily directly responsible for hallucination and psychedelic effect. Hallucinogenesis is more likely related to tonic disinhibition of neural assemblies normally stabilized by tonic feedback inhibition. In other words, 5-HT2A agonism does not cause neurons to fire, it activates cellular signaling pathways for learning and growth in the wake of stimulus, which, over time, promotes hypersensitivity and uninhibited network cross-excitability.

Layer V pyramidal cells and perceptual binding

In the human brain the highest density of 5-HT2A receptors are expressed on the dendrites of cortical layer V pyramidal cells3,4,5,6,8, and the highest density of layer V dendrites project upward into the arbors of cortical layer I, the very outward surface of the brain. 5-HT2A receptors in the dendritic arbors of pyramid cells are primarily responsible for modulating asynchronous (late) glutamate release in the wake of incoming sensory spike trains,1,11,12 presumably for enhanced top-down aliasing (reconstruction and rendering) of salient sensory data.13 Sensory signal rising to the dendrites of the cortical surface encodes a highly detailed reconstruction of external perception for latent real-time analysis and progressive perceptual filling. Multiple layers of the neocortex have descending columnar dendrites or ascending recurrent axon collaterals to provide real-time sensory feedback to apical rendering layers, allowing a seamless representation of perception to be shared across the cortex. Cortical layer V neurons receiving input through apical dendrites are one of the primary conduits for binding coherent sensory perception across the entire cortical surface of the brain.14

Layer V pyramidal cells are unique in that they mediate multiple pathways of perceptual feedback analysis.14,15 For example, in the visual cortex layer V pyramidal cells are responsible for synchronizing corticothalamic activity with the thalamic nuclei via descending axons; they mediate feedback discrimination in columnar circuits via recurrent collaterals ascending through Layers I-IV; they mediate reciprocal interareal connections via laterally branching arboreal and basilar dendrites; and they mediate afferent cortico-cortical signal flow to the pre-frontal cortex (PFC) along both dorsal and ventral processing streams. Through lateral, vertical, elliptical, and recurrent feedback connections, layer V pyramidal cells bind multisensory frame data across the cortex with a functional refresh rate of roughly 15 to 30 frames-per-second (FPS), which means these neurons must process and neutralize incoming sensory spike trains at roughly every 30-60 milliseconds.16 Loss of precise synchrony and coupling in these circuits would necessarily lead to loss of temporal fidelity in multisensory frame binding. Agonism, disinhibition, excitation, and destabilization in layer V recurrent circuits would necessarily lead to global multisensory frame aliasing errors, feedback synesthesia, and eventual perceptual overload.

Nonlinear destabilization in thalamocortical feedback loops

The most potent psychedelics are 5-HT2A receptor agonists; the highest density of 5-HT2A receptors are in the dendrites of layer V pyramidal cells; layer V pyramidal cells bind information in feedback projections throughout the brain. Taking these factors into account it is reasonable to assume that psychedelic hallucinogenic activity is due to nonlinear signal destabilization and amplification via recurrent layer V feedback projections. Psychedelic hallucination is achieved by partial or full agonism along recurrent layer V binding pathways; the introduction of a competing agonist in the 5-HT2A modulatory system leads directly to loss of localized inhibition and self-sustaining excitation of autonomic sensory binding complexes. Destabilization of layer V projections is most acute where signal travels in recurrent loops or feedback circuits that resolve incoming multisensory data in real time. The primary circuits for binding real-time frame data include the cortico-striato-thalamo-cortical (CSTC) loops, and the more distributed cortico-thalamo-cortical feedback loops (or thalmocortical loops) which pass information from the cortex through the basal ganglia and back into the thalamus for discrimination and gating of incoming signal flow to the cortex. These loops can be described as attention-controlled feedback filters which drive and stabilize external perception and behavior. CSTC loops provide real-time sensory feedback for fine-tuning eye movements, motor reflexes, emotional responses, and cognitive value placed on stimulus.17 Destabilization in signal coupling along thalamocortical feedback pathways will necessarily lead to problems with sensory gating, multisensory frame resolution, and fast temporal aliasing.

There are specific perceptual effects one would expect to see as a result of instability in thalamocortical feedback loops between the thalamus to the visual cortex, such as a subtle flickering or pulsing of light intensity; geometric grids and matrices; the perception of halos or auras around light sources; increased luminosity of reflective objects; the softening of line and texture resolution; and the inability to hold sharp focal contrast between foreground and background in depth perception.18 Sensory filling in the visual periphery relies on fast temporal aliasing of visual signal for real-time results, and this temporal aliasing can be subverted by optical illusions which create a sense of movement in the periphery. A competing 5-HT2A agonist would necessarily disrupt the precise inhibitory timing in the cortical columns needed for peripheral edge detection and sensory filling, leading to shifting line and depth ambiguities. If the rate of multisensory frame saturation or neutralization was slowed or interrupted by even a few milliseconds, incoming sensation would begin to layer over itself with increasing levels of smoothing, liquidity, and phantom frame echo decaying in the wake of sensation.19

5-HT2A receptor agonists can destabilize multisensory perception in a number of ways. The most general explanation is that 5-HT2A agonists introduce a competing excitatory impulse that disrupts the precise timing of sensory binding in the apical dendrites and recurrent circuits of the thalamus and cortex. Evidence indicates that 5-HT2A agonists promote a late release of glutamate from layer V pyramidal cells following strong incoming spike trains, resulting in the generation of asynchronous excitatory postsynaptic currents (EPSCs).1,11,12 Asynchronous EPSCs in recurrent sensory circuits are normally helpful for resolving important perceptual data, but if the subject is unable to inhibit evoked ESPCs caused by exogenous modulators (hallucinogens), this late signaling action can lead to glutamate flooding and tonic sensory saturation in perceptual neural assemblies, which is consistent with manic states of hallucinogenesis.20 There is evidence that 5-HT2A agonists lead to lateral disinhibition in the cortex by blocking presynaptic uptake of 5-HT at the lateral inhibitory synapse, or by overriding tonic GABAB inhibitory postsynaptic potentials (IPSPs) with asynchronous ESPCs at the lateral-inhibitory synapse.21,22 Loss of inhibition at the lateral synapses in columns of the visual cortex would lead directly to shifting and wiggling in peripheral line, texture, and contrast resolution. As thalamocortical feedback circuits become increasingly disinhibited they may fall into coherent self-sustaining states of underconstrained perception, promoting phantom sensory activity such as hallucination and spontaneous dream imagery.23 In the disinhibited state mild stimulus may not provoke hallucinogenic response, but intense stimulation would drive sudden localized feedback coherence, nonlinear signal amplification, and frame latency errors. The sudden shift from stabilized brain focus to states of elicited thalamocortical feedback excitation can be described in terms of a nonlinear, non-equilibrium phase transition in response to energetic sensory drivers.15

5-HT2A cross-agonism and holistic organism re-modulation

Looking beyond the cortex, it is worth mentioning that 5-HT2A receptors are also found in the midbrain, olfactory systems, the brainstem, intestines, and all over the body in smooth muscles and cardiovascular systems. There is some evidence that 5-HT2 agonists have a secondary effect at the locus ceruleans in the brainstem (LC), promoting adrenal activity in the presence of strong sensory drivers.1 Sensory driving of adrenal release may promote a synesthetic burst of emotional intensity accompanying any strong multisensory experience. There is evidence that 5-HT agonist hallucinogens inhibit sensory gating in the thalamus, allowing more raw sensation to flood the cortex;17 this is consistent with decreased gating and nonlinear feedback amplification in thalamocortical loops. A common early side-effect of hallucinogen use is stomach tightening and intestinal cramping; this is undoubtedly due to 5-HT2A agonism interfering with serotonergic modulation of smooth muscle contraction in the gut. 5-HT2A cross-agonism in the intestines can lead to nausea and purgation, and reports of intense hallucinations and peak psychedelic experiences typically increase immediately following release of intestinal discomfort.24 This indicates that radical interruption and re-modulation of all 5-HT2A pathways, from the intestines to the cortex, may be a common precursor to peak psychedelic experiences and states of bodily transcendence.

Because of the multiple systems affected by 5-HT2A receptor agonism, it would be overly reductive to point to a single pathway as being responsible for full psychedelic activation. The synergistic effect of multi-layered 5-HT2A agonism is felt subjectively as a throbbing or pulsation of energy which suffuses the entire body, builds in strength and complexity, and culminates in a cathartic multisensory release of highly charged transformative content. At the sensory level glutamate flooding saturates perception. At the emotional level adrenal response drives sensual intensity. At the frame level aminergic destabilization leads to disorientation and loss of temporal ego cohesion. At the cognitive level aminergic destabilization drives irrationality, depersonalization, and hallucinogenic dream states. At the circulatory level 5-HT2A agonism promotes vasoconstriction and increases blood pressure. At the somatic level an interruption of digestive functioning drives metabolic destabilization and energetic intracellular signaling. At the organism level the holistic effects of prolonged 5-HT2A agonism become nonlinear, meaning they begin to generate complex energetic output in response to sensory input over time. This multi-layered organism activation can be formally described as a runaway biological feedback process, or a nonlinear cellular signaling loop which drives increasing cellular coupling complexity over the duration of synergistic agonism.

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Notes and References

[1] Aghajanian GK, Marek GJ, 'Seratonin and Hallucinogens'. Neuropsychopharmacology. 1999 Aug;21(2 Suppl):16S-23S.

[2] Ray TS, 'Psychedelics and the Human Receptorome'. PLoS One. 2010; 5(2): e9019.

[3] Burnet PW, Eastwood SL, Lacey K, Harrison PJ, 'The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain'. Brain Res. 1995 Apr 3;676(1):157-68.

[4] Forutan F, Estalji S, Beu M, et al., 'Distribution of 5HT2A receptors in the human brain: comparison of data in vivo and post mortem'. Nuklearmedizin. 2002;41(4):197-201.

[5] Pompeiano M, Palacios JM, Mengod G., 'Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors'. Brain Res Mol Brain Res. 1994 Apr;23(1-2):163-78.

[6] WikiPedia.org, '5-HT2A Receptor'. Internet Reference, 2010.

[7] Azmitia EC, 'Serotonin and brain: evolution, neuroplasticity, and homeostasis'. Int Rev Neurobiol. 2007;77:31-56.

[8] Nichols DE, 'Hallucinogens'. Pharmacology & Therapeutics Volume 101, Issue 2, February 2004, Pages 131-181

[9] Urban JD, et al., 'Functional selectivity and classical concepts of quantitative pharmacology'. J Pharmacol Exp Ther. 2007 Jan;320(1):1-13. Epub 2006 Jun 27.

[10] WikiPedia.org, 'Protein kinase C'. Internet Reference, 2010.

[11] Aghajanian GK, Marek GJ, 'Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release'. Brain Research Volume 825, Issues 1-2, 17 April 1999, Pages 161-171

[12] Aghajanian GK, Marek GJ, 'Serotonin Induces Excitatory Postsynaptic Potentials in Apical Dendrites of Neocortical Pyramidal Cells '. Neuropharmacology Volume 36, Issues 4-5, 5 April 1997, Pages 589-599

[13] Spratling, M. W. , 'Cortical Region Interactions and the Functional Role of Apical Dendrites'. Behavioral and Cognitive Neuroscience Reviews 1-3 (2002) 219-228.

[14] Jones EG, 'Thalamic circuitry and thalamocortical synchrony'. Philos Trans R Soc Lond B Biol Sci. 2002 Dec 29;357(1428):1659-73.

[15] Lumer ED, Edelman GM, Tononi G, 'Neural dynamics in a model of the thalamocortical system. II. The role of neural synchrony tested through perturbations of spike timing'. Cereb Cortex. 1997 Apr-May;7(3):228-36.

[16] See "Limits of Human Perception"

[17] Vollenweider FX, Geyer MA, 'A systems model of altered consciousness: integrating natural and drug-induced psychoses'. Brain Res Bull. 2001 Nov 15;56(5):495-507.

[18] See "Entoptic Hallucination"

[19] See "Erratic Hallucination"

[20] Geyer MA, Vollenweider FX, 'Serotonin research: contributions to understanding psychoses'. Trends Pharmacol Sci. 2008 Sep;29(9):445-53.

[21] Kass L, Hartline PH, Adolph AR , 'Presynaptic uptake blockade hypothesis for LSD action at the lateral inhibitory synapse in Limulus'. The Journal of General Physiology, Vol 82, 245-267

[22] Shao Z, Burkhalter A, 'Role of GABAB receptor-mediated inhibition in reciprocal interareal pathways of rat visual cortex'. J Neurophysiol. 1999 Mar;81(3):1014-24.

[23] Behrendt RP, 'Hallucinations: synchronisation of thalamocortical gamma oscillations underconstrained by sensory input'. Conscious Cogn. 2003 Sep;12(3):413-51.

[24] Accounts of hallucinogens causing stomach unease and intestinal cramping taken from surveys of subjective reports.

[25] Watts SW, 'Activation of the mitogen-activated protein kinase pathway via the 5-HT2A receptor'. Ann N Y Acad Sci. 1998 Dec 15;861:162-8.

[26] WikiPedia.org, 'Mitogen-activated protein kinase'. Internet Reference, 2010.

[27] See “Psychedelic Neuroplasticity”

[28] Belcheva MM, et al., 'μ and κ Opioid Receptors Activate ERK/MAPK via Different Protein Kinase C Isoforms and Secondary Messengers in Astrocytes'. J Biol Chem. 2005 July 29; 280(30): 2766227669.

[29] Bohn LM, 'Mitogenic Signaling via Endogenous κ-Opioid Receptors in C6 Glioma Cells: Evidence for the Involvement of Protein Kinase C and the Mitogen-Activated Protein Kinase Signaling Cascade'. J Neurochem. 2000 February; 74(2): 564573.

[30] Bruchas MR, et al., 'Kappa Opioid Receptor Activation of p38 MAPK Is GRK3- and Arrestin-dependent in Neurons and Astrocytes'. June 30, 2006 The Journal of Biological Chemistry, 281, 18081-18089.

Citation: Kent, James L. Psychedelic Information Theory: Shamanism in the Age of Reason, Chapter 07, '5-HT2A Agonism and Multisensory Binding'. PIT Press, Seattle, 2010.

Keywords: 5-HT2A receptors, pyramidal neurons, apical dendrites

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