Prevention of dyskinesia by an NMDA receptor antagonist in MPTP monkeys: effect on adenosine A2A receptors.
Adenosine A(2A) receptors (A(2A)R) have received increasing attention for the treatment of L-DOPA-induced dyskinesias in Parkinson disease. In the present study, A(2A)R messenger RNA (mRNA) and receptor-specific binding in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys were studied after treatment with L-DOPA and a selective NR1A/2B NMDA receptor antagonist, CI-1041. Four MPTP monkeys received L-DOPA/benserazide and all developed dyskinesias, whereas among the four MPTP monkeys who additionally received CI-1041, only one developed mild dyskinesias. Four normal monkeys and four MPTP-treated monkeys were also studied. All MPTP monkeys had similar striatal dopamine (DA) denervation. A(2A)R mRNA levels, measured by in situ hybridization, were increased in the rostral lateral caudate and putamen of saline-treated MPTP monkeys as well as in the caudal lateral and medial putamen when compared with those of controls. A(2A)R mRNA levels remained elevated in the rostral caudate and putamen of L-DOPA-treated MPTP monkeys when compared with those of controls. A(2A)R mRNA levels of L-DOPA + CI-1041-treated monkeys were at control levels and decreased in the lateral rostral caudate and caudal putamen when compared with those of L-DOPA-treated and saline-treated MPTP monkeys respectively. No change was measured in the caudal medial putamen and caudate nucleus. A(2A)Rs labeled by autoradiography with [(3)H]SCH-58261 had lower level in the L-DOPA + CI-1041-treated MPTP monkeys compared with saline- or L-DOPA-treated MPTP and control monkeys in the rostral lateral and medial caudate and the putamen. No effect of lesion or L-DOPA treatment was measured on [(3)H]SCH-58261-specific binding. These findings suggest that blockade of NMDA receptors could prevent the development of dyskinesias by altering A(2A)Rs.
Morissette
Marc
M
Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre (CHUL), Quebec, Canada.
Dridi
Mehdi
M
Calon
Frédéric
F
Hadj Tahar
Abdallah
A
Meltzer
Leonard T
LT
Bédard
Paul J
PJ
Di Paolo
Thérèse
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001583:Benzoxazoles / Q000494:pharmacology*; D003714:Denervation; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D007091:Image Processing, Computer-Assisted; D017403:In Situ Hybridization; D007980:Levodopa / Q000627:therapeutic use; D008252:Macaca fascicularis; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D015345:Oligonucleotide Probes; D010052:Ovariectomy; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000517:prevention & control*; D010880:Piperidines / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents; D001583:Benzoxazoles; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D015345:Oligonucleotide Probes; D010880:Piperidines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate; D014230:Triazoles; D007980:Levodopa; C481484:besonprodil; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine