Long-term treatment with l-DOPA and an mGlu5 receptor antagonist prevents changes in brain basal ganglia dopamine receptors, their associated signaling proteins and neuropeptides in parkinsonian monkeys.
Brain glutamate overactivity is well documented in Parkinson's disease (PD) and antiglutamatergic drugs decrease L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID); the implication of dopamine neurotransmission is not documented in this anti-LID activity. Therefore, we evaluated changes of dopamine receptors, their associated signaling proteins and neuropeptides mRNA, in normal control monkeys, in saline-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in L-DOPA-treated MPTP monkeys, without or with an adjunct treatment to reduce the development of LID: 2-methyl-6-(phenylethynyl)pyridine (MPEP), the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist. All de novo treatments were administered for 1 month and the animals were sacrificed thereafter. MPTP monkeys treated with l-DOPA + MPEP developed significantly less LID than MPTP monkeys treated with l-DOPA alone. [(3)H]SCH-23390 specific binding to D1 receptors of all MPTP monkeys was decreased as compared to controls in the basal ganglia and no difference was observed between all MPTP groups, while striatal D1 receptor mRNA levels remained unchanged. [(3)H]raclopride specific binding to striatal D2 receptors and mRNA levels of D2 receptors were increased in MPTP monkeys compared to controls; l-DOPA treatment reduced this binding in MPTP monkeys while it remained elevated with the l-DOPA + MPEP treatment. Striatal [(3)H]raclopride specific binding correlated positively with D2 receptor mRNA levels of all MPTP-lesioned monkeys. Striatal preproenkephalin/preprodynorphin mRNA levels and phosphorylated ERK1/2 and Akt/GSK3β levels increased only in L-DOPA-treated MPTP monkeys as compared to controls, saline treated-MPTP and l-DOPA + MPEP treated MPTP monkeys. Hence, reduction of development of LID with MPEP was associated with changes in D2 receptors, their associated signaling proteins and neuropeptides.
Faculty of Pharmacy, Université Laval, Quebec City G1K 7P4, Canada; Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City G1V 4G2, Canada.
Nicolas
N
Morin
Faculty of Pharmacy, Université Laval, Quebec City G1K 7P4, Canada; Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City G1V 4G2, Canada.
Vincent A
VA
Jourdain
Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City G1V 4G2, Canada.
Marc
M
Morissette
Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City G1V 4G2, Canada.
Laurent
L
Grégoire
Faculty of Pharmacy, Université Laval, Quebec City G1K 7P4, Canada; Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City G1V 4G2, Canada. Electronic address: therese.dipaolo@crchul.ulaval.ca.
Thérèse
T
Di Paolo
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000494:pharmacology*; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004399:Dynorphins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007980:Levodopa / Q000009:adverse effects / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008252:Macaca fascicularis; D020734:Parkinsonian Disorders / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism
D000978:Antiparkinson Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004745:Enkephalins; D018691:Excitatory Amino Acid Antagonists; D011498:Protein Precursors; D011725:Pyridines; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C036448:pre-prodynorphin; D007980:Levodopa; D004399:Dynorphins; C121465:6-methyl-2-(phenylethynyl)pyridine; C033660:preproenkephalin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
Akt/GSK3; Dopamine receptor; ERK1/2; MPEP; Preprodynorphin; Preproenkephalin