125I-CGP 64213 binding to GABA(B) receptors in the brain of monkeys: effect of MPTP and dopaminomimetic treatments.
Much evidence indicates that abnormal GABA neurotransmission may be implicated in the pathophysiology of Parkinson's disease (PD) and dopaminomimetic-induced dyskinesias (DID). In this study, autoradiography using (125)I-CGP 64213 was performed to investigate GABA(B) receptor density in the brain of control monkeys as well as monkeys with MPTP-induced nigrostriatal depletion. Three MPTP monkeys received pulsatile administrations of the D1 dopamine (DA) receptor agonist (SKF 82958) whereas a long-acting D2 DA receptor agonist (cabergoline) was given to another three animals. SKF 82958 treatment relieved parkinsonian symptoms but two of three animals developed DID. Cabergoline induced a comparable motor benefit effect without persistent DID. (125)I-CGP 64213 binding to GABA(B) receptors was heterogeneous throughout the brain with the highest levels in the medial habenula of the thalamus. MPTP induced a decrease (-40%) of (125)I-CGP 64213 binding to GABA(B) receptors in the substantia nigra pars compacta (SNpc) and an increase (+29%) in the internal segment of the globus pallidus (GPi). This increase in the GPi was not affected by SKF 82958 but partly reversed by cabergoline. No change was seen in the striatum, the thalamus, the external segment of the globus pallidus, and the substantia nigra pars reticulata following MPTP and dopaminomimetic treatments. The changes of GABA(B) receptors observed in the SNpc and in the GPi suggest that alteration of GABA(B) receptors may play a role in the pathophysiology of PD and DID.
Calon
F
F
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), Québec, Qc, G1V 4G2, Canada.
Morissette
M
M
Goulet
M
M
Grondin
R
R
Blanchet
P J
PJ
Bédard
P J
PJ
Di Paolo
T
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001345:Autoradiography; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001552:Benzazepines / Q000494:pharmacology; D001565:Benzoates / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000077465:Cabergoline; D003342:Corpus Striatum / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000378:metabolism*; D058788:GABA-B Receptor Antagonists; D007279:Injections, Subcutaneous; D007457:Iodine Radioisotopes; D008252:Macaca fascicularis; D009943:Organophosphorus Compounds / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000978:Antiparkinson Agents; D001552:Benzazepines; D001565:Benzoates; C104981:CGP 64213; D018491:Dopamine Agonists; D004873:Ergolines; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D007457:Iodine Radioisotopes; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; C071262:SK&F 82958; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000077465:Cabergoline