Effect of metabotropic glutamate receptor activation on receptor-mediated cyclic AMP responses in primary cultures of rat striatal neurones.
Co-activation of group I metabotropic glutamate (mGlu) receptors and adenosine receptors resulted in an augmented cyclic AMP response in primary cultures of rat striatal neurones. L-glutamate and the selective group I agonist, (S)-dihydroxyphenylglycine (S-DHPG) evoked concentration-dependent potentiations of cyclic AMP accumulation stimulated by the adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), with EC50 values of 3.41+/-0. 39 and 5.69+/-1.64 microM, respectively, and maximal augmentations of approximately 350% at concentrations of 100 microM. The S-DHPG potentiation was inhibited by group I mGlu receptor antagonists and a protein kinase C inhibitor, Ro 31-8220, implicating products of PI hydrolysis in this effect. Furthermore, L-glutamate and S-DHPG stimulated PI hydrolysis in striatal neuronal cultures with similar EC50 values to those observed for the augmentation of NECA cyclic AMP responses (5.19+/-1.18 and 3.78+/-1.42 microM, respectively). In situ hybridization and immunofluorescence techniques indicate that group I mGlu receptor-evoked potentiations are likely to be mediated via mGlu5 receptors, which are expressed at high levels in these cultures. In contrast to cross-chopped slices of neonatal rat striatum, of equivalent age, the group II mGlu receptor agonist, (2S, 2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) was without effect on NECA- or forskolin-stimulated cyclic AMP responses in primary striatal neuronal cultures. This lack of effect might be due to a low level of expression of group II mGlu receptors in cultured striatal neurones.
Cartmell
J
J
Pharma Division, Preclinical CNS Research, F. Hoffmann-La Roche, CH 4070 Basel, Switzerland.
Goepfert
F
F
Knoflach
F
F
Pink
J R
JR
Bleuel
Z
Z
Richards
J G
JG
Schaffhauser
H
H
Kemp
J A
JA
Wichmann
J
J
Mutel
V
V
D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006868:Hydrolysis; D017403:In Situ Hybridization; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012118:Resorcinols / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D019830:Adenosine-5'-(N-ethylcarboxamide); D018698:Glutamic Acid; C079215:3,5-dihydroxyphenylglycine; D000242:Cyclic AMP; D005998:Glycine