Psychotogenic drugs and delirium pathogenesis: the central role of the thalamus
Introduction
Numerous data – albeit indirect – link cholinergic and dopaminergic pathways to delirium pathophysiology. An excess of central dopaminergic activity and/or a deficit in brain cholinergic activity would elicit delirium [1]. Yet, other brain systems are thought to be involved in delirium pathophysiology, such as γ-amino-butyric acid (GABA) and glutamatergic diffuse modulatory pathways [2]. Whether their contribution is an epiphenomenon or the cornerstone of the pathophysiologic mechanisms of delirium remains to be established. Countless psychoactive drugs that can interfere through their mechanism of action with the brain diffuse modulatory systems are psychotomimetic, inducing delirium-like states. Based on a diverse body of evidence from research in schizophrenia, hepatic encephalopathy, alcohol/amphetamine/opioid dependence, we propose in this paper a unified theoretical model of delirium pathogenesis that explores the mechanisms by which various psychoactive drugs acting on cholinergic, dopaminergic, GABAergic, and glutamatergic modulatory systems are psychotogenic. Drugs that temporarily hamper the ability of the thalamus to filter the relevant information that travels to the cortex would induce a transitory psychotic state, id est delirium.
Section snippets
Unitary theory model of delirium: temporary thalamic filtering dysfunction
Dysfunctions in acetylcholine or dopamine neurotransmission could alone account for certain symptomatic manifestations of delirium (e.g. attention or memory deficits, hallucinations). Yet, these systems interact through various anatomical structures (cortex, striatum, thalamus) with, inter alia, GABAergic and glutamatergic modulatory systems. The genesis of psychosis could depend on an interplay between the neurotransmission pathways bridging these structures [3].
The thalamus plays a key role
Mechanisms of drug-induced delirium
Pharmacological agents that increase cortical GABAergic activity, such as GABAA receptor agonists and benzodiazepines, reduce corticostriatal glutamatergic tone. This could lead to psychosis through a reduction of the inhibitory striatothalamic GABAergic influence [3]. Muscimol, the psychoactive alkaloid extracted from the mushroom Amanita muscaria – which has been known and used for its hallucinogenic properties since prehistoric times [10], is an example of a GABAA receptor agonist acting on
Future directions
The history of the development of numerous psychotropic drugs points up the fact that major scientific discoveries can evolve as a consequence of clinical investigation, rather than deductions from basic animal research [24]. Elucidation of the mechanism of action of antidepressants and antipsychotics, for instance, provided new insights into the underlying pathophysiology of depression and schizophrenia, respectively, by a form of “inverse reasoning” since their effectiveness in the treatment
Acknowledgements
Preparation of this manuscript was supported in part by awards to the first author from the Fonds d’Enseignement et de Recherche of the Faculty of Pharmacy, Laval University and from the Canadian Institutes of Health Research – National Cancer Institute of Canada (NCIC) Strategic Training Program in Palliative Care research. Pierre Gagnon is a Research Scientist of the Canadian Cancer Society through an award from the NCIC.
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2017, Medical HypothesesCitation Excerpt :Sanders suggest that some drugs may influence inhibitory tone within brain networks, which may reduce their connectivity and function [1]. Opioids, benzodiazepines and anticholinergics, among others, have the potential to alter thalamic and striatal function [27], which may disrupt SN function and DMN/DAN switching/anticorrelation. One thing which appears to be common among many drugs with a high potential to precipitate delirium is their ability to significantly impact on one or another component of the SN.