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. 2025 Mar;45(1):e12524.
doi: 10.1002/npr2.12524.

Co-Expression of Tardive Dyskinesia and Drug-Induced Parkinsonism in Rats Chronically Treated With Haloperidol

Iku Kinoshita  1   2 , Haruo Nishijima  1   2 , Takashi Nakamura  1 , Tomoya Kon  1 , Shuji Shimoyama  3 , Hiroki Hikichi  1 , Chieko Suzuki  1 , Masahiko Tomiyama  1
Affiliations

Co-Expression of Tardive Dyskinesia and Drug-Induced Parkinsonism in Rats Chronically Treated With Haloperidol

Iku Kinoshita et al. Neuropsychopharmacol Rep. 2025 Mar.

Abstract

Aim: We aimed to create a rat model of drug-induced parkinsonism and tardive dyskinesia by chronic administration of haloperidol and examine the expression of direct and indirect pathway markers in the striatum of the model rats.

Methods: We treated 21 rats, 14 with haloperidol decanoate and 7 with placebo. The number of vacuous chewing movements per 2 min was counted, and haloperidol-treated rats were classified into two groups: mild and severe tardive dyskinesia. Other behavioral analyses were also conducted. After a 6-month treatment period, rat brains were removed, and protein expression was evaluated by Western blotting.

Results: All haloperidol-treated rats exhibited vacuous chewing movements. The frequency of exploratory behavior and rotarod test performance was lower in the mild and severe tardive dyskinesia groups. The number of vacuous chewing movements and frequency of exploratory behavior were positively correlated in haloperidol-treated rats. The expression of dynorphin, a direct pathway marker, decreased in the severe tardive dyskinesia group. The expression of enkephalin, an indirect pathway marker, decreased both in the mild and severe tardive dyskinesia groups. The expression of dopamine D1 and D2 receptors also decreased with haloperidol treatment.

Conclusion: Both direct and indirect pathways are involved in haloperidol-induced movement disorders.

Keywords: direct pathway; dopamine D1 receptor; dopamine D2 receptor; dynorphin; enkephalin; indirect pathway; vacuous chewing movement.

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Conflict of interest statement

Haruo Nishijima received a research grant from Sumitomo Pharma Co. Ltd. The other authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this study.

Figures

FIGURE 1
FIGURE 1
Behavioral analyses in chronic haloperidol‐treated rats. (A) Vacuous chewing movements (VCMs) per 2 min gradually increased with repeated haloperidol treatment in the severe TD group. (B) The frequency of exploratory behavior decreased after treatment initiation. (C) Performance in the rotarod test deteriorated with haloperidol treatment. Statistical analysis was performed only for week 27. (D) There was a positive correlation between the number of VCMs and the frequency of exploratory behaviors in haloperidol‐treated rats. (E) There was no association between the number of VCMs and rotarod test performance in haloperidol‐treated rats. *p < 0.05 and **p < 0.01 compared with the control group; +p < 0.05 and ++p < 0.01 compared with mild TD group via Kruskal–Wallis and post hoc Steel–Dwass tests. Error bars represent the standard error of the mean. TD, tardive dyskinesia.
FIGURE 2
FIGURE 2
Western blot analyses of rat striatal tissue. (A, B) Dynorphin A expression was decreased in the severe TD group. (C, D) Enkephalin expression was decreased in the mild and severe TD groups. (E, F) TH expression was not significantly different among groups. *p < 0.05; **p < 0.01 via one‐way ANOVA and post hoc Dunnett tests. Error bars represent the standard error of the mean. GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; TD, tardive dyskinesia; TH, tyrosine hydroxylase.
FIGURE 3
FIGURE 3
Western blot analyses of rat striatal tissue. (A, B) Dopamine D1 receptor expression was decreased in the mild and severe TD groups. (C, D) Dopamine D2 receptor expression was also decreased in the mild and severe TD groups. *p < 0.05; **p < 0.01 via one‐way ANOVA and post hoc Dunnett tests. Error bars represent the standard error of the mean. GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; TD, tardive dyskinesia.
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