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 approximately 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 D(3)/D(2) 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 D(2)/D(3) 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.