Effects of the prototypical mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats

In the present study, we evaluated the effect of the prototypical metabotro pic glutamate receptor 5 (mGlu(5)) antagonist 2-methyl-6-(phenylethynyl)-py ridine (MPEP) on motor behaviour in rats using the accelerating rotarod, sp ontaneous locomotor activity and the 6-hydroxy-dopamine (6-OHDA) lesion mod el to assess its treatment potential for Parkinson's disease. The data indi cate that MPEP at doses between 7.5 and 300 mg/kg, p.o. did not disrupt end urance performance on the accelerating rotarod (4-40 rpm in 300 s) which in dicates that MPEP has a relatively high safety margin. However, while ineff ective at doses of 3.75, 7.5 and 15 mg/kg (p.o.) MPEP inhibited spontaneous locomotor activity at doses of 30 and 100 mg/kg (p.o.). In the 6-OKDA rat rotation model, at doses of 7.5, 15 and 30 mg/kg (p.o.), MPEP induced a dos e-dependent ipsilateral rotational response that reached statistical signif icance at the highest dose tested. This effect was relatively small but con sistent. In combination with direct or indirect dopamine agonists, i.e. apo morphine (0.25 mg/kg, s.c.) and D-amphetamine (2.5 mg/kg, i.p.), MPEP(7.5, 15 or 30 mg/kg, p.o.) was found to significantly inhibit these dopamine rec eptor mediated rotational responses. MPEP injected at a dose of 30 mg/kg al so inhibited the rotational response induced by L-DOPA (25 mg/kg, i.p.). ()MK-801 was used in these rotation experiments as the reference compound. I n view of these findings, it could be concluded that MPEP and potentially o ther mGlu(5) receptor antagonists are probably not appropriate drug candida tes for the symptomatic treatment of Parkinson's disease. (C) 2000 Elsevier Science B.V. All rights reserved.