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 hyperactiv ity of glutamatergic neurotransmission. In the search for a therapy of Park inson's disease, ionotropic, mainly NMDA, receptor antagonists were found t o have moderately beneficial, yet also some undesirable side-effects. There fore the present study was aimed at determining whether some metabotropic g lutamate receptor (mGluR) ligands may have antiparkinsonian effects in the haloperidol-induced muscle rigidity. To this end three mGluR ligands were u sed: the potent and selective mGluR I antagonist (RS)-1-aminoindan-1,5-dica rboxylic acid (AIDA), the mixed group II agonist/group I antagonist (S)-4-c arboxy-3-hydroxyphenyl-glycine ((S)-4-C3HPG), and the potent group II agoni st (+)-2-aminobicyclo[3.1.0.]hexane-2,6,dicarboxylic acid (LY354740). Only LY354740 penetrated the brain from the periphery; for this reason other dru gs were injected bilaterally into the rostral striatum or nucleus accumbens . The muscle tone was recorded by a mechanomyographic/electromyographic (MM G/EMG) method which measured the resistance of a rat's hind foot and the EM G reflex response of its muscles to passive movements. (S)-4C3KPG (5 and 15 mu g/0.5 mu l) and LY354740 (5 and 10 mg/kg i.p.) diminished the muscle ri gidity induced by haloperidol (1 mg/kg i.p.). AIDA (0.5-15 mu g/0.5 mu l) i njected into the striatum was only slightly effective in the highest dose u sed. However, when injected into the nucleus accumbens AIDA (15 mu g/0.5 mu l) 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 rigidi ty. However, it seems that the antagonism of group I mGluRs located in the nucleus accumbens may also be of importance to the antiparkinsonian effect.