Differential roles of mGlu8 receptors in the regulation of glutamate and gamma-aminobutyric acid release at periaqueductal grey level.
We investigated the role of group III metabotropic glutamate (mGlu) receptors on glutamate and GABA releases at the periaqueductal grey (PAG) level by using in vivo microdialysis in rats. Intra-PAG perfusion of either L-(+)-2-amino-4-phosphonobutyric acid (L-AP4, 100-300 microM), (RS)-4-phosphonophenylglycine ((RS)-PPG, 100-300 microM) selective agonists of group III mGlu receptors, or (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG, 50-100 microM), a selective agonist of mGlu8 receptor, increased glutamate and decreased GABA extracellular concentrations. (RS)-alpha-methylserine-O-phosphate (MSOP, 0.5 mM), a selective group III receptor antagonist, perfused in combination with (S)-3,4-DCPG, L-AP4 or (RS)-PPG, antagonised the effects induced by these agonists on both extracellular glutamate and GABA values. alpha-Methyl-3-methyl-4-phosphonophenylglycine (UBP1112, 300 microM), a group III mGlu receptor antagonist, perfused in combination with (RS)-PPG or (S)-3,4-DCPG, antagonised the effects induced by these agonists. Intra-PAG perfusion with forskolin (100 microM), an activator of adenylate cyclase, increased dialysate glutamate and GABA levels. Moreover, intra-PAG perfusion with N-[2-(p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89) (100 microM), a protein kinase (PKA) inhibitor, abolished the effect of (S)-3,4-DCPG on both glutamate and GABA releases. H-89, per se, did not modify glutamate release but reduced extracellular GABA value at the higher dosage used (200 microM). These data suggest that group III mGlu receptors in the PAG modulate the releases of glutamate and GABA conversely. In particular, both the facilitation of glutamate and the inhibition of GABA releases require the participation of coupling to adenylate cyclase and the subsequent activation of the PKA pathway.
Marabese
Ida
I
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Faculty of Medicine and Surgery, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
de Novellis
Vito
V
Palazzo
Enza
E
Mariani
Loredana
L
Siniscalco
Dario
D
Rodella
Luigi
L
Rossi
Francesco
F
Maione
Sabatino
S
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000613:Aminobutyrates / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D017551:Microdialysis / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010768:Phosphoserine / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C110733:3,4-dicarboxyphenylglycine; C119327:4-phosphonophenylglycine; D000613:Aminobutyrates; D001565:Benzoates; D004338:Drug Combinations; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; C101185:alpha-methyl-4-phosphonophenylglycine; C111435:metabotropic glutamate receptor 8; C120877:methylserine phosphate; D010768:Phosphoserine; D005576:Colforsin; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C012729:2-amino-4-phosphonobutyric acid; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000409:Alanine; D005998:Glycine