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

• MPTP lesion increased striatal 5-HIAA levels and left 5-HT levels unchanged.
• Striatal and pallidal 5-HT2A receptors increased in l-DOPA-treated MPTP monkeys.
• l-DOPA+MPEP treatment left striatal 5-HT2A receptors unchanged.
• Dyskinesias correlated with striatal and pallidal 5-HT2A receptor levels.
• l-DOPA+MPEP treatment left 5-HT1A receptor and 5-HT transporter levels unchanged.

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-HT1A and 5-HT2A 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. [3H]-8-OH-DPAT and [3H]-citalopram specific binding levels to 5-HT1A 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. [3H]-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.