Fig. 1: LRRK2 mediates the effects of haloperidol on movement disruption.

A Schematic of the experiment and treatment schedule. Catalepsy was assessed with the bar test, and distance traveled was recorded in an open-field arena; both were performed 1 hr after the final treatment administration. Treatment conditions: Vehicle for MLi-2, 40% 2-hydroxypropyl-β-cyclodextrin; MLi2, 10 mg/kg; vehicle for PFE-360, 1.25% hydroxypropyl cellulose + 0.5% docusate sodium; PFE- 360, 5 mg/kg; vehicle for haloperidol, saline (0.9% NaCl); haloperidol, 1 mg/kg. Some schematics were created with BioRender.com. X-axis: vehicle = vehicle for MLi-2 + vehicle for haloperidol; haloperidol = vehicle for MLi-2 + haloperidol; MLi-2 or PFE-360 = MLi- 2 or PFE-360 + vehicle for haloperidol; MLi-2 or PFE-360 + haloperidol, as indicated. All drugs were administered intraperitoneally (i.p.) except MLi-2, PFE-360, and their vehicles, which were given orally. B Cataleptic response of WT mice receiving haloperidol, MLi-2, their combination, and vehicle controls for 7 days. N = 9, 15, 8, 13 mice, in order of groups presented. C Same as B, but using PFE-360 and its corresponding vehicle. N = 8, 9, 6, 6 mice, in order of groups presented. D Cataleptic response of LRRK2-WT and LRRK2-KO mice receiving haloperidol or control vehicle for 7 days. N = 11 mice for both genotypes. E Cataleptic response of Drd2^fl/fl and Drd2^fl/fl; Adora2a^cre mice receiving haloperidol for 7 days. N = 9 and 15 mice, respectively. F Distance traveled in the open-field test for WT mice receiving haloperidol or haloperidol + MLi-2. N = 8 and 9 mice, respectively. Data are represented as mean ± SEM. Asterisks in B, C show statistical significance for Tukey’s multiple comparison tests after one-way ANOVA; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Asterisks in D–F show statistical significance for unpaired t-test comparison; **p < 0.01,***p < 0.001, ****p < 0.0001. Error bars as SEM.