Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonists proved to be effective in alleviating experimental parkinsonism. Nonetheless, loss of effectiveness or even worsening of parkinsonian symptoms have been observed at high doses. With the aim of clarifying the circuitry underlying the dual action of NOP receptor antagonists and the role of endogenous dopamine, the NOP receptor antagonist 1-benzyl-N-[3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl]pyrrolidine-2-carboxamide (Compound 24) and the D2/D3 receptor antagonist raclopride were used in 6-hydroxydopamine hemilesioned rats. Systemically administered Compound 24 improved motor activity in the 0.1-10mg/kg dose range being ineffective at 30mg/kg. To confirm NOP selectivity, Compound 24 improved motor performance in wild-type mice at 1 and 10mg/kg and inhibited it at 60mg/kg, being ineffective in NOP receptor knockout mice. To prove that the bell-shaped profile was mediated by nigral NOP receptors, reverse dialysis of Compound 24 (0.03μM) in substantia nigra reticulata ameliorated akinesia whereas Compound 24 (3μM) was ineffective. To demonstrate that motor responses were mediated by tuning inhibitory and excitatory inputs to nigro-thalamic neurons, the low concentration elevated GABA and reduced glutamate in substantia nigra, simultaneously reducing GABA levels in ventro-medial thalamus. Conversely, the higher concentration reduced nigral and elevated thalamic GABA, without affecting nigral glutamate levels. Co-perfusion with raclopride (1μM) abolished the antiakinetic action of Compound 24 (0.03μM) and turned the ineffectiveness of Compound 24 (3μM) into an antiakinetic effect. The low concentration reduced nigral but did not affect thalamic GABA whereas the higher concentration elevated nigral and reduced thalamic GABA. Neither concentration affected nigral glutamate. We conclude that dual motor effects of Compound 24 in hemiparkinsonian rats are accomplished through blockade of nigral NOP receptors resulting in opposite modulation of nigro-thalamic neurons. Endogenous dopamine contributes to these responses affecting the level of GABAergic inhibition of the nigral output via D2/D3 receptors. © 2010 Elsevier Inc.
Dopamine-nociceptin/orphanin FQ interactions in the substantia nigra reticulata of hemiparkinsonian rats: Involvement of D2/D3 receptors and impact on nigro-thalamic neurons and motor activity
VOLTA, Mattia;MORARI, Michele
2011
Abstract
Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonists proved to be effective in alleviating experimental parkinsonism. Nonetheless, loss of effectiveness or even worsening of parkinsonian symptoms have been observed at high doses. With the aim of clarifying the circuitry underlying the dual action of NOP receptor antagonists and the role of endogenous dopamine, the NOP receptor antagonist 1-benzyl-N-[3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl]pyrrolidine-2-carboxamide (Compound 24) and the D2/D3 receptor antagonist raclopride were used in 6-hydroxydopamine hemilesioned rats. Systemically administered Compound 24 improved motor activity in the 0.1-10mg/kg dose range being ineffective at 30mg/kg. To confirm NOP selectivity, Compound 24 improved motor performance in wild-type mice at 1 and 10mg/kg and inhibited it at 60mg/kg, being ineffective in NOP receptor knockout mice. To prove that the bell-shaped profile was mediated by nigral NOP receptors, reverse dialysis of Compound 24 (0.03μM) in substantia nigra reticulata ameliorated akinesia whereas Compound 24 (3μM) was ineffective. To demonstrate that motor responses were mediated by tuning inhibitory and excitatory inputs to nigro-thalamic neurons, the low concentration elevated GABA and reduced glutamate in substantia nigra, simultaneously reducing GABA levels in ventro-medial thalamus. Conversely, the higher concentration reduced nigral and elevated thalamic GABA, without affecting nigral glutamate levels. Co-perfusion with raclopride (1μM) abolished the antiakinetic action of Compound 24 (0.03μM) and turned the ineffectiveness of Compound 24 (3μM) into an antiakinetic effect. The low concentration reduced nigral but did not affect thalamic GABA whereas the higher concentration elevated nigral and reduced thalamic GABA. Neither concentration affected nigral glutamate. We conclude that dual motor effects of Compound 24 in hemiparkinsonian rats are accomplished through blockade of nigral NOP receptors resulting in opposite modulation of nigro-thalamic neurons. Endogenous dopamine contributes to these responses affecting the level of GABAergic inhibition of the nigral output via D2/D3 receptors. © 2010 Elsevier Inc.
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