Abstract
Antipsychotics often cause tardive dyskinesia, an adverse symptom of involuntary hyperkinetic movements. Analysis of the US Food and Drug Administration Adverse Event Reporting System and JMDC insurance claims revealed that acetaminophen prevented the dyskinesia induced by dopamine D2 receptor antagonists. In vivo experiments further showed that a 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) in rats, an effect that was inhibited by oral acetaminophen treatment or intracerebroventricular injection of N-(4-hydroxyphenyl)-arachidonylamide (AM404), an acetaminophen metabolite that acts as an activator of the transient receptor potential vanilloid 1 (TRPV1). In mice, haloperidol-induced VCMs were also mitigated by treatment with AM404 applied to the dorsal striatum, an effect not seen in TRPV1-deficient mice. Acetaminophen prevented the haloperidol-induced decrease in the number of c-Fos+preproenkephalin+ striatal neurons in wild-type mice but not in TRPV1-deficient mice. Finally, chemogenetic stimulation of indirect pathway medium spiny neurons in the dorsal striatum decreased haloperidol-induced VCMs. These results suggest that acetaminophen activates the indirect pathway neurons by activating TRPV1 channels via AM404.
Highlights
Dyskinesia is a neurological symptom characterized by involuntary muscle movements of the tongue, lower face, jaw, and/or extremities
We investigated the association between the use of drugs and the incidence of dyskinesia in FDA Adverse Event Reporting System (FAERS) data via disproportionality analysis by calculating the reporting odds ratio (ROR) and its z score
This study shows for the first time that centrally acting antinociceptive and antipyretic acetaminophen mitigates orofacial dyskinesia induced by the long-term use of D2 receptor (D2R) antagonists
Summary
Dyskinesia is a neurological symptom characterized by involuntary muscle movements of the tongue, lower face, jaw, and/or extremities. There are 2 types of drug-induced dyskinesia that result from different pathogenic situations: the levodopa-induced dyskinesia that occurs in patients with Parkinson’s disease and tardive dyskinesia (TD) that occurs due to long-term use of dopamine D2 receptor (D2R) antagonists, such as antipsychotics. Dyskinesia occurs spontaneously as a hyperkinetic symptom of Huntington’s disease and is considered related to the degeneration or malfunction of indirect pathway medium spiny neurons (iMSNs) within the striatum [1]. TD emerges after prolonged use of antipsychotics in 20% to 30% of cases, and its symptoms become irreversible after long-term use of D2R antagonists [2]. Various clinical treatments using cholinergic agents, such as amantadine, β-adrenergic blockers, GABA agonists, or antioxidants have been explored as therapeutic strategies to prevent or alleviate TD [3]; there is insufficient evidence to support their use in the management of TD. The development of new strategies to reduce the risk of TD remains a priority
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