title: The metabotropic glutamate receptor 8 agonist (S)-3,4-DCPG reverses motor deficits in prolonged but not acute models of Parkinson's disease.
abstract: Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Kari A
authors.initials: KA
authors.lastname: Johnson
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Tantawy
authors.forename: Michael
authors.initials: M
authors.lastname: Bubser
authors.forename: Marketa
authors.initials: M
authors.lastname: Marvanova
authors.forename: M Sib
authors.initials: MS
authors.lastname: Ansari
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Baldwin
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
mesh_terms: D000613:Aminobutyrates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006220:Haloperidol; D007276:Injections, Intraventricular; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*; D012110:Reserpine; D013997:Time Factors
chemical_list: C110733:3,4-dicarboxyphenylglycine; D000613:Aminobutyrates; D001565:Benzoates; D065127:Dopamine D2 Receptor Antagonists; D018690:Excitatory Amino Acid Agonists; D017448:Receptors, Dopamine D2; D018094:Receptors, Metabotropic Glutamate; C111435:metabotropic glutamate receptor 8; D012110:Reserpine; C012729:2-amino-4-phosphonobutyric acid; D006220:Haloperidol; D005998:Glycine; D004298:Dopamine