Dual motor response to L-dopa and nociceptin/orphanin FQ receptor antagonists in
1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) treated mice: Paradoxical
inhibition is relieved by D2/D3 receptor blockade
Motor activity of mice acutely treated with the parkinsonian toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine
(MPTP) was monitored for 6 days using behavioral tests which provide complementary
information on motor function: the bar, reaction time, drag, stair climbing, grip, rotarod and footprinting
tests. These tests consistently disclosed a prolonged motor impairment characterized by akinesia,
bradykinesia, speed reduction, loss of coordination and gait patterns. This impairment was associated
with ∼60% loss of striatal dopamine terminals, as revealed by tyrosine hydroxylase immunohistochemistry,
and was attenuated by dopaminergic drugs. Indeed, the dopamine precursor, L-dopa (1–10 mg/kg), and the
D3/D2 receptor agonist pramipexole (0.0001–0.001 mg/kg) promoted stepping activity in the drag test (a
test for akinesia/bradykinesia). The novel nociceptin/orphanin FQ receptor (NOP) antagonist 1-[1-
(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4-pyridinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-
2-one (Trap-101, 0.001–0.1 mg/kg), an analogue of 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-
4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397), also promoted stepping and
synergistically or additively (depending on test) attenuated parkinsonism when combined to dopamine
agonists. High doses of L-dopa (100 mg/kg), pramipexole (0.1 mg/kg), Trap-101 and J-113397 (1 mg/kg),
however, failed to modulate stepping, worsening immobility time and/or rotarod performance. Low doses
of amisulpride (0.1 mg/kg) reversed motor inhibition induced by L-dopa and J-113397, suggesting
involvement of D2/D3 receptors. This study brings further evidence for a dopamine-dependent motor
phenotype in MPTP-treated mice reinforcing the view that this model can be predictive of symptomatic
antiparkinsonian activity provided the appropriate test is used. Moreover, it offers mechanistic
interpretation to clinical reports of paradoxical worsening of parkinsonism following L-dopa. Finally, it
confirms that NOP receptor antagonists may be proven effective in reversing parkinsonism when
administered alone or in combination with dopamine agonists
