ly-341495 and Dyskinesia--Drug-Induced

Metabotropic glutamate 5 (mGlu5) receptor antagonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LID) in Parkinson's disease (PD). The aim of this study was to investigate the long-term effect of the prototypal mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on glutamate receptors known to be involved in the development of LID in the de novo chronic treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with L-DOPA and developed dyskinesias while those treated with L-DOPA and MPEP (10 mg/kg) developed significantly less. Normal control and saline-treated MPTP monkeys were also included. All MPTP monkeys were extensively and similarly denervated. The basal ganglia [(3)H]ABP688 specific binding (mGlu5 receptors) was elevated in L-DOPA-treated MPTP monkeys compared to controls but not in those treated with L-DOPA and MPEP; dyskinesia scores of these monkeys correlated positively with their [(3)H]ABP688 specific binding. Striatal density (B(max)) of [(3)H]ABP688 specific binding increased in L-DOPA-treated MPTP monkeys compared to other groups and affinity (Kd) remained unchanged. Striatal mGlu5 receptor mRNA remained unchanged following treatments. Elevated basal ganglia specific binding of [(3)H]Ro 25-6981 (NMDA NR1/NR2B receptors), [(3)H]Ro 48-8587 (AMPA receptors) but not [(3)H]CGP-39653 (NMDA NR1/NR2A receptors) was observed only in L-DOPA-treated MPTP monkeys; dyskinesias scores correlated with binding. By contrast, basal ganglia [(3)H]LY341495 specific binding (mGlu2/3 receptors) decreased in L-DOPA-treated MPTP monkeys compared to controls, saline and L-DOPA + MPEP treated MPTP monkeys; dyskinesias scores correlated negatively with this binding. Hence, chronic MPEP treatment reduces the development of LID and is associated with a normalization of glutamate neurotransmission.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Basal Ganglia; Corpus Striatum; Dyskinesia, Drug-Induced; Female; Imidazoles; Levodopa; Macaca fascicularis; Oximes; Parkinsonian Disorders; Phenols; Piperidines; Pyridines; Quinazolines; Radioligand Assay; Receptor, Metabotropic Glutamate 5; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Tritium; Xanthenes

Modulation of basal ganglia group II metabotropic glutamate receptors (mGluR2/3) is a potential therapeutic alternative to levodopa in Parkinson disease (PD). We used receptor-binding autoradiography of the mGluR2/3-selective radioligand [H]LY341495 in postmortem brain specimens from PD patients (n = 14) and controls (n=11) to investigate possible contributions of changes in ligand binding of this receptor to levodopa-associated motor complications experienced premortem in PD patients. The PD patients included those with and without histories of dyskinesias and those with and without "wearing off," which is defined as a reduced period of benefit from levodopa. Specific binding of [H]LY341495 to mGluR2/3 in the basal ganglia was higher in the caudate nucleus than the putamen and lower by approximately half in the external and internal globus pallidus (GPi) in controls. [H]LY341495-specific binding was reduced in the caudate and GPi in patients without wearing-off (-22% caudate, -30% GPi), compared with controls and with patients who had experienced wearing-off; there were no differences among PD patients with or without dyskinesias. These data suggest that an adaptive downregulation of mGluR2/3 in PD patients without wearing-off may compensate for increased glutamate. They indicate a key role for mGluR2/3 in control of movement and the potential for mGluR2/3-targeted drugs in the management of wearing-off fluctuations in PD.

Topics: Aged; Aged, 80 and over; Amino Acids; Antiparkinson Agents; Brain; Cocaine; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Female; Humans; Iodine Radioisotopes; Levodopa; Male; Parkinsonian Disorders; Postmortem Changes; Radioligand Assay; Receptors, Metabotropic Glutamate; Tritium; Xanthenes

L-Dopa-induced dyskinesias (LIDs), the disabling abnormal involuntary movements induced by chronic use of L-Dopa, limit the quality of life in Parkinson's disease (PD) patients. Modulation of group II metabotropic glutamate receptors (mGluR2/3) in the basal ganglia, a brain region critically involved in motor control, is considered as an alternative approach in therapy of PD. In this study, receptor binding autoradiography of [3H]LY341495, a mGluR2/3 selective radioligand, was used to investigate possible changes in mGluR2/3 in the basal ganglia of L-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys having developed LIDs compared to animals in which LIDs were prevented by adjunct treatments with CI-1041, a selective antagonist of the NR1A/2B subtype of NMDA receptor, or low doses of the dopamine D2 receptor agonist, cabergoline. Our study is the first to provide evidence of: (1) the similar localization of [3H]LY341495 specific binding to mGluR2/3 in the primate basal ganglia as compared to receptor distribution measured by immunohistochemistry in human and rat as well as this ligand binding in intact rat brain; (2) no change of [3H]LY341495 specific binding in basal ganglia after nigrostriatal denervation by MPTP; and (3) a widespread reduction of [(3)H]LY341495 specific binding to mGluR2/3 in the caudate nucleus (-17% to -31%), putamen (-12% to -45%) and globus pallidus (-56 to -59%) of non-dyskinetic animals treated with L-Dopa+cabergoline as compared to controls, MPTP monkeys treated with saline, L-Dopa alone (dyskinetic) or L-Dopa+CI-1041 (non-dyskinetic). This study is the first to propose a close interaction between mGluR2/3 and dopamine D2 receptors activation in the basal ganglia.

Topics: Amino Acids; Animals; Antiparkinson Agents; Autoradiography; Basal Ganglia; Behavior, Animal; Cabergoline; Caudate Nucleus; Data Interpretation, Statistical; Dyskinesia, Drug-Induced; Ergolines; Excitatory Amino Acid Antagonists; Female; Levodopa; Macaca fascicularis; Ovariectomy; Putamen; Receptors, Metabotropic Glutamate; Xanthenes