Effect of a chronic treatment with an mGlu5 receptor antagonist on brain serotonin markers in parkinsonian monkeys.

TitleEffect of a chronic treatment with an mGlu5 receptor antagonist on brain serotonin markers in parkinsonian monkeys.
Publication TypeJournal Article
Year of Publication2015
AuteursMorin, N, Morissette, M, Grégoire, L, Di Paolo, T
JournalProg Neuropsychopharmacol Biol Psychiatry
Volume56
Pagination27-38
Date Published2015 Jan 02
ISSN1878-4216
Keywords1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 3,4-Dihydroxyphenylacetic Acid, Animals, Benserazide, Brain, Disease Models, Animal, Dopamine, Dopamine Agents, Dose-Response Relationship, Drug, Drug Combinations, Dyskinesia, Drug-Induced, Excitatory Amino Acid Antagonists, Female, Homovanillic Acid, Levodopa, Macaca fascicularis, Ovariectomy, Parkinsonian Disorders, Protein Binding, Pyridines, Serotonin
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.

DOI10.1016/j.pnpbp.2014.07.006
Alternate JournalProg. Neuropsychopharmacol. Biol. Psychiatry
PubMed ID25046277
Grant ListMOP-114916 / / Canadian Institutes of Health Research / Canada