title: Effect of a chronic treatment with an mGlu5 receptor antagonist on brain serotonin markers in parkinsonian monkeys.
abstract: In Parkinson's disease (PD) and l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs), overactivity of brain glutamate neurotransmission is documented and antiglutamatergic drugs decrease LID. Serotonin (5-HT) receptors and transporter (SERT) are also implicated in LID and we hypothesize that antiglutamatergic drugs can also regulate brain serotoninergic activity. Our aim was to investigate the long-term effect of the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) with L-DOPA on basal ganglia SERT, 5-HT(1A) and 5-HT(2A) receptor levels in monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with L-DOPA and developed LID while those treated with L-DOPA and MPEP (10 mg/kg) developed significantly less LID. Normal controls and saline-treated MPTP monkeys were included for biochemical analysis. The MPTP lesion and experimental treatments left unchanged striatal 5-HT concentrations. MPTP lesion induced an increase of striatal 5-HIAA concentrations similar in all MPTP monkeys as compared to controls. [(3)H]-8-OH-DPAT and [(3)H]-citalopram specific binding levels to 5-HT(1A) receptors and SERT respectively remained unchanged in the striatum and globus pallidus of all MPTP monkeys compared to controls and no difference was observed between groups of MPTP monkeys. [(3)H]-ketanserin specific binding to striatal and pallidal 5-HT2A receptors was increased in L-DOPA-treated MPTP monkeys as compared to controls, saline and L-DOPA+MPEP MPTP monkeys and no difference between the latter groups was observed; dyskinesia scores correlated positively with this binding. In conclusion, reduction of development of LID with MPEP was associated with lower striatal and pallidal 5-HT2A receptors showing that glutamate activity also affects serotoninergic markers.
authors.affiliation: Faculty of Pharmacy, Université Laval, 1050 Avenue de la Médecine, Quebec City G1V 0A6, Canada; Neuroscience Research Unit, Centre de Recherche du CHU de Québec, 2705 Laurier Boulevard, 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, 2705 Laurier Boulevard, Quebec City G1V 4G2, Canada. Electronic address: marc.morissette@crchudequebec.ulaval.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.affiliation: Neuroscience Research Unit, Centre de Recherche du CHU de Québec, 2705 Laurier Boulevard, Quebec City G1V 4G2, Canada. Electronic address: laurent.gregoire@crchudequebec.ulaval.ca.
authors.forename: Laurent
authors.initials: L
authors.lastname: Grégoire
authors.affiliation: Faculty of Pharmacy, Université Laval, 1050 Avenue de la Médecine, Quebec City G1V 0A6, Canada; Neuroscience Research Unit, Centre de Recherche du CHU de Québec, 2705 Laurier Boulevard, Quebec City G1V 4G2, Canada. Electronic address: therese.dipaolo@crchudequebec.ulaval.ca.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001545:Benserazide / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism; D015259:Dopamine Agents / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000627:therapeutic use; D008252:Macaca fascicularis; D010052:Ovariectomy; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D012701:Serotonin / Q000378:metabolism*
chemical_list: D015259:Dopamine Agents; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; C005177:benserazide, levodopa drug combination; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D007980:Levodopa; D001545:Benserazide; C121465:6-methyl-2-(phenylethynyl)pyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C001746:3-methoxytyramine; D004298:Dopamine; D006719:Homovanillic Acid
keywords: Basal ganglia; MPEP; MPTP monkey; Serotonin receptor; Serotonin transporter; l-DOPA-induced dyskinesia