Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonist–induced orofacial dyskinesia
Koki Nagaoka, … , Hisashi Shirakawa, Shuji Kaneko
Koki Nagaoka, … , Hisashi Shirakawa, Shuji Kaneko
Published April 15, 2021
Citation Information: JCI Insight. 2021;6(10):e145632. https://doi.org/10.1172/jci.insight.145632.
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Research Article Neuroscience

Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonist–induced orofacial dyskinesia

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.

Authors

Koki Nagaoka, Takuya Nagashima, Nozomi Asaoka, Hiroki Yamamoto, Chihiro Toda, Gen Kayanuma, Soni Siswanto, Yasuhiro Funahashi, Keisuke Kuroda, Kozo Kaibuchi, Yasuo Mori, Kazuki Nagayasu, Hisashi Shirakawa, Shuji Kaneko

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Figure 4

Effects of intracerebral AM404 on haloperidol-induced VCMs in rodents.

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Effects of intracerebral AM404 on haloperidol-induced VCMs in rodents. (...
(A) Rats (n = 5–7 per group) were treated daily with oral haloperidol (1 mg/kg/d) for 21 days and received AM404 (0, 10, or 50 nmol) via intracerebroventricular injection at 23 hours after the last administration of haloperidol. The number of VCMs was measured for 3 minutes starting 30 minutes after the administration of AM404. After the experiment, the injection sites were confirmed by injecting Evans blue through the same cannula. A representative image of consecutive coronal sections is shown (43 mm wide in actual size). Individual data are shown with the mean ± SEM. Statistical significance was tested using 1-way ANOVA with post hoc Tukey’s test. *P < 0.05, **P < 0.01, ***P < 0.001. (B) Mice (n = 8 per group) were treated daily with oral haloperidol (2 mg/kg/d) for 21 days. On day 22, after VCMs were counted for 5 minutes as an initial baseline, half of the mice received vehicle (group 1), and the rest received AM404 (0.5 pmol/side; group 2) through a preimplanted cannula in the dorsal striatum. After 5 minutes, the number of VCMs was counted for another 5 minutes to determine the effect of the injected substance. The daily haloperidol treatment was continued for 4 more days; on day 26, the second set of VCM measurements was performed in a crossover design, with AM404 injection in group 1 and vehicle injection in group 2. After the experiment, the injection sites were confirmed by Evans blue staining through the same cannula. A representative image of the coronal section is shown (11.5 mm wide in actual size). Changes in the number of VCMs are represented for individual mice on days 22 and 26 as a percentage of the baseline VCM count. Open and filled circles indicate the results from groups 1 and 2, respectively. Statistical significance was tested using 2-tailed paired t test. **P < 0.01.