Psychotogenic drugs and delirium pathogenesis: the central role of the thalamus

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Summary

Delirium is thought to be a temporary psychiatric disorder resulting from a reduced central cholinergic transmission, combined with an increased dopaminergic transmission. The cholinergic and the dopaminergic systems interact not only with each other but with glutamatergic and γ-amino-butyric acid (GABA) pathways. Besides the cerebral cortex, critical anatomical substrates of psychosis pathophysiology would comprise the striatum, the substantia nigra/ventral tegmental area, and the thalamus. The thalamus acts as a filter, allowing only the relevant information to travel to the cortex. Drugs of abuse (e.g. PCP, Ecstasy), as well as psychoactive medications frequently prescribed to hospitalized patients (e.g. benzodiazepines, opioids) could compromise the thalamic gating function, leading to sensory overload and hyperarousal. We propose that drug-induced delirium would result from the transient thalamic dysfunction caused by exposure to medications that interfere with central glutamatergic, GABAergic, dopaminergic and cholinergic pathways at critical sites of action. This model provides directions for future studies in neurophysiology, in vivo brain imaging, and psychopharmacology investigating delirium neuropathophysiology.

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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