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benzimidazol-2-one), either injected intranigrally or given systemically, also elevated striatal dopamine release and facilitated motor activity, confirming that these effects were caused by blockade of endogenous N/OFQ signaling. The inhibitory role played by endogenous N/OFQ on motor activity was additionally strengthened by the finding that mice lacking the NOP receptor gene outperformed wild-type mice on the rotarod. We conclude that NOP receptors in the substantia nigra pars reticulata, activated by endogenous N/OFQ, drive a physiologically inhibitory control on motor behavior, possibly via modulation of the nigrostriatal dopaminergic pathway.

Metabotropic glutamate receptor type 5 (mGluR5) modulates dopamine and glutamate neurotransmission at central synapses. In this study, we addressed the role of mGluR5 in L-DOPA-induced dyskinesia, a movement disorder that is due to abnormal activation of both dopamine and glutamate receptors in the basal ganglia. A selective and potent mGluR5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine, was tested for its ability to modulate molecular, behavioural and neurochemical correlates of dyskinesia in 6-hydroxydopamine-lesioned rats treated with L-DOPA. The compound significantly attenuated the induction of abnormal involuntary movements (AIMs) by chronic L-DOPA treatment at doses that did not interfere with the rat physiological motor activities. These effects were paralleled by an attenuation of molecular changes that are strongly associated with the dyskinesiogenic action of L-DOPA (i.e. up-regulation of prodynorphin mRNA in striatal neurons). Using in vivo microdialysis, we found a temporal correlation between the expression of L-DOPA-induced AIMs and an increased GABA outflow within the substantia nigra pars reticulata. When co-administered with L-DOPA, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine greatly attenuated both the increase in nigral GABA levels and the expression of AIMs. These data demonstrate that mGluR5 antagonism produces strong anti-dyskinetic effects in an animal model of Parkinson's disease through central inhibition of the molecular and neurochemical underpinnings of L-DOPAinduced dyskinesia.

By using a battery of behavioral tests, we showed that nociceptin/orphanin FQ receptor (NOP receptor) antagonists attenuated parkinsonian-like symptoms in 6-hydroxydopamine hemilesioned rats (Marti et al., 2005). We now present evidence that coadministration of the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397) and L-DOPA to 6-hydroxydopamine hemilesioned rats produced an additive attenuation of parkinsonism. To investigate the neurobiological substrates underlying this interaction, in vivo microdialysis was used in combination with behavioral measurements (bar test). J-113397 and L-DOPA alone reduced the time on bars (i.e., attenuated akinesia) and elevated GABA release selectively in the lesioned substantia nigra reticulata. J-113397 also reduced nigral glutamate levels, whereas L-DOPA was ineffective. J-113397 and L-DOPA coadministration produced additive antiakinetic effect, which was associated with additive increase in nigral GABA release but no additional reductions in glutamate levels. To investigate whether the increase in nigral GABA release could translate to changes in nigrothalamic transmission, GABA release was monitored in the ventromedial thalamus (one of the main target areas of the nigrothalamic projections). J-113397 and L-DOPA decreased thalamic GABA release and attenuated akinesia, their combination resulting in a more profound effect. These actions were prevented by perfusing the voltage-dependent Na ϩ channel blocker tetrodotoxin or the GABA A receptor antagonist bicuculline in the substantia nigra reticulata. These data demonstrate that J-113397 and L-DOPA exert their antiparkinsonian action through overinhibition of nigrothalamic transmission and suggest that NOP receptor antagonists may be useful as an adjunct to L-DOPA therapy for Parkinson's disease.