The depolarization-induced outflow of D-[3H]aspartate from rat brain slices is modulated by metabotropic glutamate receptors.
Rat brain slices were used to study the effects of different metabotropic glutamate receptor ligands on (i) the depolarization (30 mM KCl)-induced outflow of previously taken up D-[3H]aspartate; (ii) the inhibition of forskolin (30 microM)-induced cyclic AMP accumulation; and (iii) the hydrolysis of phosphoinositides. In addition, the localization of mRNAs coding for different metabotropic glutamate receptor subtypes was detected using in situ hybridization. (1S-3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (30-300 microM), a non selective metabotropic glutamate receptor agonist, significantly increased the KCl-induced output of radioactivity from cortical slices, whereas it inhibited the output from striatal slices. Conversely, (1S,3S,4S)-carboxycyclopropylglycine (0.1-1 microM), a relatively selective agonist of the mGluR2 metabotropic glutamate receptor subtype, had an inhibitory effect on the output of D-[3H]aspartate from both cortical and striatal slices and proved to be the most potent metabotropic glutamate receptor agonist in inhibiting cyclic AMP accumulation, but not in stimulating phosphoinositide hydrolysis. Since 2-amino-4-phosphonobutyrate (a mGluR4, mGluR6 and mGluR7 agonist) was not active in any of the assays tested, we hypothesized that the mGluR2 subtype could be involved in these events. Accordingly, mGluR2 mRNA expression was abundant in cortical neurons projecting to the striatum. Our experiments suggest that the stimulation of metabotropic glutamate receptors may either decrease or increase transmitter release depending on the subtype that prevails in the region under study.
Lombardi
G
G
Dipartimento di Farmacologia Preclinica, Università di Firenze, Italy.
Pellegrini-Giampietro
D E
DE
Leonard
P
P
Cherici
G
G
Pellicciari
R
R
Moroni
F
F
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D015347:RNA Probes; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D009498:Neurotoxins; D010716:Phosphatidylinositols; D015347:RNA Probes; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D001224:Aspartic Acid; D016318:Quisqualic Acid; D000242:Cyclic AMP; D011188:Potassium