Background and purpose
Increased firing of the glutamatergic pathway between the subthalamic nucleus and substantia nigra pars reticulata (SNpr) contributes to the abnormal firing of motor circuits and subsequent motor deficits seen in Parkinson's disease. Broad spectrum agonist-induced activation of presynaptic group III metabotropic glutamate (mGlu) receptors within the SNpr reduced glutamate release and reversed akinesia in the reserpine-treated rat model of Parkinson's disease. Here, we have sought to identify which subtypes of group III mGlu receptor in the SNpr were responsible for these beneficial effects. Experimental approach: The ability of the mGlu(4) positive allosteric modulator, N-phenyl-7-(hydroxyminocyclopropa[b]chromen-1a-carboxamide) (PHCCC), the mGlu(7) allosteric agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) and the mGlu(8) -selective agonist (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG] to inhibit KCl-evoked [(3) H]-D-aspartate release was examined in vitro in rat nigral prisms. Reversal of akinesia in reserpine-treated rats was also assessed following intranigral injection of these agents. Key
Purpose
Increased firing of the glutamatergic pathway between the subthalamic nucleus and substantia nigra pars reticulata (SNpr) contributes to the abnormal firing of motor circuits and subsequent motor deficits seen in Parkinson's disease. Broad spectrum agonist-induced activation of presynaptic group III metabotropic glutamate (mGlu) receptors within the SNpr reduced glutamate release and reversed akinesia in the reserpine-treated rat model of Parkinson's disease. Here, we have sought to identify which subtypes of group III mGlu receptor in the SNpr were responsible for these beneficial effects. Experimental approach: The ability of the mGlu(4) positive allosteric modulator, N-phenyl-7-(hydroxyminocyclopropa[b]chromen-1a-carboxamide) (PHCCC), the mGlu(7) allosteric agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) and the mGlu(8) -selective agonist (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG] to inhibit KCl-evoked [(3) H]-D-aspartate release was examined in vitro in rat nigral prisms. Reversal of akinesia in reserpine-treated rats was also assessed following intranigral injection of these agents. Key
Results
PHCCC and AMN082 inhibited [(3) H]-D-aspartate release by 42% and 53%, respectively when given alongside a sub-threshold concentration of the broad spectrum group III agonist, L-2-amino-4-phosphonobutyrate (L-AP4; 1 µM). In contrast (S)-3,4-DCPG failed to inhibit [(3) H]-D-aspartate release. All three agents also reversed reserpine-induced akinesia although only the effects of PHCCC and AMN082 were inhibited by pre-treatment with the group III antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG). Conclusions and implications: These findings reveal that targeting SNpr mGlu(4) or mGlu(7) receptors, but not mGlu(8) receptors, provided relief from akinesia in the reserpine-treated rat model of Parkinson's disease, most likely reflecting inhibition of excess glutamate release in this region.