Auditory mismatch responses are differentially sensitive to changes in muscarinic acetylcholine versus dopamine receptor function

The auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Such dysfunction may be caused by aberrant interactions of different neuromodulators with NMDARs, which could explain clinical heterogeneity among patients. In two studies (...

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Bibliographic Details
Published in:eLife 2022-05, Vol.11
Main Authors: Weber, Lilian Aline, Tomiello, Sara, Schöbi, Dario, Wellstein, Katharina V, Mueller, Daniel, Iglesias, Sandra, Stephan, Klaas Enno
Format: Article
Language:English
Subjects:
acetylcholine
Acetylcholine - pharmacology
Acetylcholine receptors (muscarinic)
Acoustic Stimulation
Auditory system
Biomarkers
Blindness
Cholinergic Agents
Clinical trials
Dopamine
Dopamine - pharmacology
Dopamine D2 Receptor Antagonists - pharmacology
Dopamine D2 receptors
Dopamine D3 receptors
Electroencephalography
Evoked Potentials, Auditory - physiology
Galantamine
Glutamic acid receptors
Glutamic acid receptors (ionotropic)
Hearing
Humans
Levodopa
Mental disorders
Mismatch negativity
Muscarinic Antagonists - pharmacology
N-Methyl-D-aspartic acid receptors
Neuromodulation
Neuroscience
NMDA receptor
Pharmacokinetics
Psychotropic drugs
Receptors, Dopamine
Schizophrenia
Volatility
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Summary:The auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Such dysfunction may be caused by aberrant interactions of different neuromodulators with NMDARs, which could explain clinical heterogeneity among patients. In two studies (N = 81 each), we used a double-blind placebo-controlled between-subject design to systematically test whether auditory mismatch responses under varying levels of environmental stability are sensitive to diminishing and enhancing cholinergic vs. dopaminergic function. We found a significant drug × mismatch interaction: while the muscarinic acetylcholine receptor antagonist biperiden delayed and topographically shifted mismatch responses, particularly during high stability, this effect could not be detected for amisulpride, a dopamine D2/D3 receptor antagonist. Neither galantamine nor levodopa, which elevate acetylcholine and dopamine levels, respectively, exerted significant effects on MMN. This differential MMN sensitivity to muscarinic versus dopaminergic receptor function may prove useful for developing tests that predict individual treatment responses in schizophrenia.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.74835