Metabotropic glutamate 7 receptor subtype modulates motor symptoms in rodent models of Parkinson's disease.

Abstract

Metabotropic glutamate (mGlu) receptors modulate synaptic transmission in the central nervous system and represent promising therapeutic targets for symptomatic treatment of Parkinson's disease (PD). Among the eight mGlu receptor subtypes, mGlu7 receptor is prominently expressed in the basal ganglia, but its role in restoring motor function in animal models of PD is not known. The effects of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the first selective allosteric activator of mGlu7 receptors, were thus tested in different rodent models of PD. Here, we show that oral (5 mg/kg) or intrastriatal administration (0.1 and 0.5 nmol) of AMN082 reverses haloperidol-induced catalepsy in rats. AMN082 (2.5 and 5 mg/kg) reduces apomorphine-induced rotations in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. In a more complex task commonly used to evaluate major akinetic symptoms of PD patients, 5 mg/kg AMN082 reverses the increased reaction time to respond to a cue of bilateral 6-OHDA-lesioned rats. In addition, AMN082 reduces the duration of haloperidol-induced catalepsy in a mGlu7 receptor-dependent manner in wild-type but not mGlu7 receptor knockout mice. Higher doses of AMN082 (10 and 20 mg/kg p.o.) have no effect on the same models of PD. Overall these findings suggest that mGlu7 receptor activation can reverse motor dysfunction associated with reduced dopamine activity. Selective ligands of mGlu7 receptor subtypes may thus be considered as promising compounds for the development of antiparkinsonian therapeutic strategies.

• Authors: B Greco, S Lopez, H van der Putten, P J Flor, M Amalric
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 332 Issue 3 Pg. 1064-71 (Mar 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 19940105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzhydryl Compounds
• N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride
• Receptors, Metabotropic Glutamate
• metabotropic glutamate receptor 7
• Oxidopamine
• Haloperidol
• Apomorphine

Topics

• Allosteric Regulation
• Animals
• Apomorphine (pharmacology)
• Benzhydryl Compounds (pharmacology)
• Catalepsy (chemically induced, physiopathology)
• Disease Models, Animal
• Haloperidol
• Male
• Mice
• Mice, Knockout
• Oxidopamine
• Parkinson Disease, Secondary (chemically induced, physiopathology)
• Rats
• Rats, Wistar
• Reaction Time (drug effects)
• Receptors, Metabotropic Glutamate (agonists, genetics, physiology)
• Stereotyped Behavior (drug effects)