J-113397 (0.03–10 mg/kg, i.p.) dually modulated rotarod performance in naïve Swiss and C57BL/6J mice. Mice were trained daily on the rotarod until their motor performance was reproducible (see Materials and methods). On the day of the experiment, three behavioral sessions were carried out, before (control session) and after (10 and 60 min) drug administration. The time spent on the rod was calculated (in seconds). Data are expressed as percent of the performance in the control session and represent the mean ±SEM of 8–10 determinations for each group. *p<0.05; different from saline (RM ANOVA followed by contrast analysis and the sequentially rejective Bonferroni’s test).

MPTP administration produced motor impairment and loss of striatal DA terminals in C57BL/6J mice. Motor activity was evaluated by three behavioral tests: the bar (panel A), drag (panel B) and rotarod (panel C) test. Mice were trained daily for a week until their motor activity was reproducible (see Materials and methods). Before MPTP (20 mg/kg) or saline administration (4 injections, 90 min apart), motor activity was evaluated, and the time spent (seconds) on the blocks (bar test), the number of steps made by the forelimbs (drag test) and the time spent on the rod (rotarod test) were calculated. Another session was repeated 7 days after MPTP administration. Tyrosine hydroxylase (TH) immunohistochemistry was then performed in striatal slices (panels D—F). Photomicrograph of TH-positive fibres in the striata of saline (panel D) and MPTP-injected (panel E) mice. Optical density of TH-positive fibres in the striatum (panel F). Values are presented as means±SEM, obtained from 4 saline- and 6 MPTP-treated mice. Data are expressed in absolute values and are mean±SEM of 9 determinations for each group. *p<0.05; different from saline-injected mice (panels A—C, ANOVA followed by the Newman—Keuls test; panel F, Student’s t-test).

J-113397 attenuated motor deficits in MPTP-treated C57BL/6J mice. Motor activity was evaluated by three behavioral tests: the bar (panel A), drag (panel B) and rotarod (panel C) test. Mice were trained daily until their motor activity was reproducible (see Materials and methods), then they were treated with MPTP. Seven days after MPTP mice were challenged with saline, J-113397 (0.01–1 mg/kg, i.p.) or L-DOPA (10 mg/kg plus benserazide 2.5 mg/kg, i.p.). Three behavioral sessions were carried out, before (control session) and after (10 and 60 min) drug or saline administration. The time spent (seconds) on the blocks (bar test), the number of steps made by the forelimbs (drag test) and the time spent on the rod (rotarod test) were calculated. Data are expressed as percent of the performance in the control session and are mean±SEM of 8–10 determinations for each group. *p<0.05; different from saline (RM ANOVA followed by contrast analysis and the sequentially rejective Bonferroni’s test).

J-113397 (0.1–3 mg/kg, i.m.) modulated motor activity in naïve nonhuman primates. Motor performance was evaluated in the Movement Analysis Panel (MAP) test. Average time in seconds to retrieve a treat in the straight rod (panel A) test was significantly improved in 2 animals at the higher dose of J-113397 tested, but at this dose the other 2 animals showed side effects (distractibility, scratching and “wet dog” shakes) and failed to perform. These 2 animals were subsequently tested in the platform (easier) task (panel B) of the MAP test in which they performed significantly worse at the high dose. *p<0.05; different from saline (ANOVA followed by PLSD test).

Effect of J-113397 on the MAP test in MPTP-treated primates. MPTP induced a significant increase in the time needed to complete the platform task (animals were unable to perform the straight rod task) in 3 out of 4 animals (Mf23, Mf25 and Mf30). In these animals L-DOPA improvement on task performance was significant. Only one of them (Mf23) showed a significant improvement in response to J-113397. *p<0.05; different from post-MPTP performance (ANOVA followed by PLSD test). ^#p<0.05; different from J-113397 (ANOVA followed by PLSD test).

Motor effects of J-113397 were dependent on NOP receptor. J-113397 (0.03–10 mg/kg, i.p.) dually modulated rotarod performance in wild-type mice (NOP^+/+; panel A) but was ineffective in NOP receptor knockout mice (NOP^−/−; panel B). Mice were trained daily on the rotarod until their motor performance was reproducible (see Materials and methods). On the day of the experiment, three behavioral sessions were carried out, before (control session) and after (10 and 60 min) drug administration. The time (in seconds) spent on the rod was calculated. Data are expressed as percent of the performance in the control session and are mean±SEM of 8–10 determinations for each group. *p<0.05; different from saline (RM ANOVA followed by contrast analysis and the sequentially rejective Bonferroni’s test).

Effect of J-113397 on motor symptoms in MPTP-treated primates. Panel A. Effect of J-113397 (0.01 mg/kg) and L-DOPA (30 mg/kg) on the global PRS score. The average improvement over the baseline score (n=2–3 pharmacological tests for each compound) is shown for each animal. The improvement after J-113397 administration (∼19±3%) was more moderate than that achieved with L-DOPA (∼46±3%, Fisher PLSD p=0.001). Comparative analysis of the pharmacological effects of L-DOPA and J-113397 on parkinsonian symptoms (panel B) showed that all symptoms improved more with L-DOPA except for hypokinesia.