Endogenous nociceptin/orphanin FQ (N/OFQ) contributes to haloperidol-induced changes of nigral amino acid transmission and parkinsonism: a combined microdialysis and behavioral study in naïve and nociceptin/orphanin FQ receptor knockout mice

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 [Nphe¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ (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.