Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy.
OBJECTIVE
Unilateral subthalamotomy is a surgical procedure that may be used to alleviate disabling levodopa-induced dyskinesias (LIDs) in patients with Parkinson disease (PD). However, the mechanisms involved in LID remain largely unknown. The subthalamic nucleus (STN) is the sole glutamatergic nucleus within the basal ganglia, and its lesion may produce changes in glutamate receptors in various areas of the basal ganglia. The authors aimed to investigate the biochemical changes in glutamate receptors in striatal and pallidal regions of the basal ganglia after lesion of the STN in parkinsonian macaque monkeys.


METHODS
The authors treated 12 female ovariectomized monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, treated 8 of these animals with 3,4-dihydroxy-l-phenylalanine (L-DOPA; levodopa) to induce LID, and performed unilateral subthalamotomy in 4 of these 8 monkeys. Four additional monkeys were treated with saline only and were used as controls. The MPTP monkeys had previously been shown to respond behaviorally to lower doses of levodopa after the STN lesion. Autoradiography of slices from postmortem brain tissues was used to visualize changes in the specific binding of striatal and pallidal ionotropic glutamate receptors (that is, of the α-amino-3-hydroxy 5-methyl-4-isoxazole propionate [AMPA] and N-methyl-d-aspartate [NMDA] NR1/NR2B subunit receptors) and of metabotropic glutamate (mGlu) receptors (that is, mGlu2/3 and mGlu5 receptors). The specific binding and distribution of glutamate receptors in the basal ganglia of the levodopa-treated, STN-lesioned MPTP monkeys were compared with those in the saline-treated control monkeys and in the saline-treated and levodopa-treated MPTP monkeys.


RESULTS
The autoradiographic results indicated that none of the pharmacological and surgical treatments produced changes in the specific binding of AMPA receptors in the basal ganglia. Levodopa treatment increased the specific binding of NMDA receptors in the basal ganglia. Subthalamotomy reversed these increases in the striatum, but in the globus pallidus (GP), the subthalamotomy reversed these increases only contralaterally. Levodopa treatment reversed MPTP-induced increases in mGlu2/3 receptors only in the GP. mGlu2/3 receptor-specific binding in the striatum and GP decreased bilaterally in the levodopa-treated, STN-lesioned MPTP monkeys compared with the other 3 groups. Compared with mGlu5 receptor-specific binding in the control monkeys, that of the levodopa-treated MPTP monkeys increased in the dorsal putamen and remained unchanged in the caudate nucleus and in the GP.


CONCLUSIONS
These results implicate glutamate receptors in the previously observed benefits of unilateral subthalamotomy to improve motor control.
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec; and.|Faculty of Pharmacy, Laval University, Quebec, Canada.
Vincent A
VA
Jourdain
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec; and.|Faculty of Pharmacy, Laval University, Quebec, Canada.
Nicolas
N
Morin
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec; and.
Laurent
L
Grégoire
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec; and.
Marc
M
Morissette
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec; and.|Faculty of Pharmacy, Laval University, Quebec, Canada.
Thérèse
T
Di Paolo
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001479:Basal Ganglia / Q000378:metabolism; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000378:metabolism* / Q000601:surgery; D005260:Female; D007980:Levodopa / Q000009:adverse effects*; D008251:Macaca; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D017470:Receptors, Glutamate / Q000378:metabolism*; D020531:Subthalamic Nucleus / Q000601:surgery*
D000978:Antiparkinson Agents; D017470:Receptors, Glutamate; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
6-OHDA = 6-hydroxydopamine; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GP = globus pallidus; GPe = GP externus; GPi = GP internus; LID = levodopa-induced dyskinesia; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP monkey; NMDA = N-methyl-d-aspartate; PD = Parkinson disease; Parkinson disease; STN = subthalamic nucleus; functional neurosurgery; glutamate receptor; levodopa; levodopa-induced dyskinesia; mGlu = metabotropic glutamate; subthalamotomy