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 metabotropic glutamate receptor 5 (mGlu(5)) antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on motor behaviour in rats using the accelerating rotarod, spontaneous locomotor activity and the 6-hydroxy-dopamine (6-OHDA) lesion model to assess its treatment potential for Parkinson's disease. The data indicate that MPEP at doses between 7.5 and 300 mg/kg, p.o. did not disrupt endurance performance on the accelerating rotarod (4-40 rpm in 300 s) which indicates that MPEP has a relatively high safety margin. However, while ineffective 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-OHDA rat rotation model, at doses of 7.5, 15 and 30 mg/kg (p.o.), MPEP induced a dose-dependent ipsilateral rotational response that reached statistical significance at the highest dose tested. This effect was relatively small but consistent. In combination with direct or indirect dopamine agonists, i.e. apomorphine (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 receptor mediated rotational responses. MPEP injected at a dose of 30 mg/kg also 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. In view of these findings, it could be concluded that MPEP and potentially other mGlu(5) receptor antagonists are probably not appropriate drug candidates for the symptomatic treatment of Parkinson's disease.
Spooren
W P
WP
Novartis Pharma AG, Nervous System Research, Klybeckstr. 141, WKL-126.3.64, CH-4002, Basel, Switzerland. willibrordus.spooren@pharma.novartis.com
Gasparini
F
F
Bergmann
R
R
Kuhn
R
R
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012399:Rotation
D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D007980:Levodopa; D016291:Dizocilpine Maleate; C121465:6-methyl-2-(phenylethynyl)pyridine; D016627:Oxidopamine; D001058:Apomorphine; D003913:Dextroamphetamine