title: Antiparkinsonian potential of targeting group III metabotropic glutamate receptor subtypes in the rodent substantia nigra pars reticulata.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Broadstock
authors.forename: P J
authors.initials: PJ
authors.lastname: Austin
authors.forename: M J
authors.initials: MJ
authors.lastname: Betts
authors.forename: S
authors.initials: S
authors.lastname: Duty
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism*; D012110:Reserpine; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D012110:Reserpine