The role of metabotropic glutamate receptor (mGluR) ligands in parkinsonian muscle rigidity.
It has been shown that the primary striatal dopaminergic hypofunction which is at the origin of Parkinson's disease, results in a secondary hyperactivity of glutamatergic neurotransmission. In the search for a therapy of Parkinson's disease, ionotropic, mainly NMDA, receptor antagonists were found to have moderately beneficial, yet also some undesirable side-effects. Therefore the present study was aimed at determining whether some metabotropic glutamate receptor (mGluR) ligands may have antiparkinsonian effects in the haloperidol-induced muscle rigidity. To this end three mGluR ligands were used: the potent and selective mGluR I antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), the mixed group II agonist/ group I antagonist (S)-4-carboxy-3-hydroxyphenyl-glycine ((S)-4-C3HPG), and the potent group II agonist (+)-2-aminobicyclo[3.1.0.]hexane-2,6,-dicarboxylic acid (LY354740). Only LY354740 penetrated the brain from the periphery; for this reason other drugs were injected bilaterally into the rostral striatum or nucleus accumbens. The muscle tone was recorded by a mechanomyographic/electromyographic (MMG/EMG) method which measured the resistance of a rat's hind foot and the EMG reflex response of its muscles to passive movements. (S)-4C3HPG (5 and 15 microg/0.5 microl) and LY354740 (5 and 10mg/kg i.p.) diminished the muscle rigidity induced by haloperidol (1 mg/kg i.p.). AIDA (0.5-15 microg/0.5 microl) injected into the striatum was only slightly effective in the highest dose used. However, when injected into the nucleus accumbens AIDA (15microg/0.5microl) significantly and strongly counteracted the haloperidol-induced muscle rigidity. Our results suggest that stimulation of group II striatal mGluRs seems to play a major role in diminution of parkinsonian-like muscle rigidity. However, it seems that the antagonism of group I mGluRs located in the nucleus accumbens may also be of importance to the antiparkinsonian effect.
Wolfarth
S
S
Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków.
Konieczny
J
J
Lorenc-Koci
E
E
Ossowska
K
K
Pilc
A
A
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D004576:Electromyography; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D009127:Muscle Rigidity / Q000503:physiopathology*; D010300:Parkinson Disease / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D001643:Bridged Bicyclo Compounds; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; C078245:4-carboxy-3-hydroxyphenylglycine; C104753:eglumetad; D005998:Glycine