The contribution of endogenous
nociceptin/orphanin FQ (N/OFQ) to
neuroleptic-induced
parkinsonism has been evaluated in
haloperidol-treated mice. Pharmacological blockade of N/
OFQ receptors (NOP) via systemic administration of 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H
benzimidazol-2-one (
J-113397, 0.01-10 mg/kg i.p.) or central injection of [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-101, 10 nmol i.c.v.) attenuated (0.8 mg/kg)
haloperidol-induced motor deficits as evaluated by a battery of behavioral tests providing complementary information on motor parameters: the bar, drag and rotarod tests. A combined neurochemical and behavioral approach was then used to investigate whether the substantia nigra reticulata could be involved in antiakinetic actions of
J-113397. Microdialysis combined to the bar test revealed that
haloperidol (0.3 and 0.8 mg/kg i.p.) caused a dose-dependent and prolonged elevation of immobility time (i.e. akinesia) which was associated with an increase in nigral
glutamate and a reduction in
GABA release. Conversely,
J-113397 (1 mg/kg) alone reduced
glutamate and elevated nigral
GABA release, and when challenged against
haloperidol, counteracted its behavioral and neurochemical effects. Microdialysis coupled to behavioral testing also demonstrated that NOP receptor knockout mice were resistant to
haloperidol (0.3 mg/kg) compared to wild-type mice, lack of response being associated with a reversal of
glutamate release facilitation into inhibition and no change in nigral
GABA release. This study provides pharmacological and genetic evidence that endogenous N/OFQ contributes to
haloperidol-induced akinesia and changes of
amino acid transmission in mice. Moreover, it confirms the view that NOP receptor antagonists are capable of reversing akinesia across species and genotypes and may prove effective in relieving
neuroleptic-induced
parkinsonism.