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

• Published in: eLife Vol. 11
• Main Authors: Weber, Lilian Aline, Tomiello, Sara, Schöbi, Dario, Wellstein, Katharina V, Mueller, Daniel, Iglesias, Sandra, Stephan, Klaas Enno
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 03.05.2022; eLife Sciences Publications, Ltd
• 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; mismatch negativity; neuroscience; acetylcholine; schizophrenia; volatility; NMDA receptor; dopamine; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.74835

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.