title: Brain α7 nicotinic acetylcholine receptors in MPTP-lesioned monkeys and parkinsonian patients.
abstract: L-DOPA-induced dyskinesias (LID) appear in the majority of Parkinson's disease (PD) patients. Nicotinic acetylcholine (nACh) receptor-mediated signaling has been implicated in PD and LID and modulation of brain α7 nACh receptors might be a potential therapeutic target for PD. This study used [(125)I]α-Bungarotoxin autoradiography to investigate α7 nACh receptors in LID in post-mortem brains from PD patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist; it reduced the development of LID in these monkeys. [(125)I]α-Bungarotoxin specific binding to striatal and pallidal α7 nACh receptors were only increased in L-DOPA-treated dyskinetic MPTP monkeys as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesia scores correlated positively with this binding. The total group of Parkinsonian patients had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus but not in the putamen. PD patients without motor complications had higher [(125)I]α-Bungarotoxin specific binding compared to controls only in the caudate nucleus. PD patients with LID only had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus and compared to those without motor complications and controls in the putamen. PD patients with wearing-off only, had [(125)I]α-Bungarotoxin specific binding at control values in the caudate nucleus and lower in the putamen. Reduced motor complications were associated with normal striatal α7 nACh receptors, suggesting the potential of this receptor to manage motor complications in PD.
authors.affiliation: Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City G1V 4G2, Canada. Electronic address: marc.morissette@crchudequebec.ulaval.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.affiliation: 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: nicolas.morin.4@ulaval.ca.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Morin
authors.affiliation: Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City G1V 4G2, Canada. Electronic address: laurent.gregoire@crchudequebec.ulaval.ca.
authors.forename: Laurent
authors.initials: L
authors.lastname: Grégoire
authors.affiliation: Division of Neurology, University of Saskatchewan, Royal University Hospital, Saskatoon, SK S7N 0W8, Canada. Electronic address: ahr128@campus.usask.ca.
authors.forename: Alex
authors.initials: A
authors.lastname: Rajput
authors.affiliation: Division of Neurology, University of Saskatchewan, Royal University Hospital, Saskatoon, SK S7N 0W8, Canada. Electronic address: Ali.Rajput@saskatoonhealthregion.ca.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Rajput
authors.affiliation: 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.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D002038:Bungarotoxins / Q000378:metabolism; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007457:Iodine Radioisotopes; D007980:Levodopa / Q000009:adverse effects; D008252:Macaca fascicularis; D008297:Male; D009928:Organ Specificity; D010052:Ovariectomy; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011699:Putamen / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D002038:Bungarotoxins; D018691:Excitatory Amino Acid Antagonists; D007457:Iodine Radioisotopes; D011725:Pyridines; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007980:Levodopa; C121465:6-methyl-2-(phenylethynyl)pyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Human; L-DOPA-induced dyskinesia; MPTP-lesioned monkey; Parkinson’s disease; α7 nicotinic acetylcholine receptor