Group-II metabotropic glutamate receptors negatively modulate NMDA transmission at striatal cholinergic terminals: role of P/Q-type high voltage activated Ca++ channels and endogenous dopamine.
Striatal cholinergic nerve terminals express functional group-II metabotropic (mGlu) and NMDA glutamate receptors. To investigate whether these receptors interact to regulate ACh release, LY354740 (a group-II mGlu receptor agonist) and NMDA were co-applied in striatal synaptosomes and slices. LY354740 prevented the NMDA-evoked [3H]-choline release from synaptosomes and ACh release from slices. In synaptosomes, this modulation was prevented by omega-agatoxin IVA, suggesting that it was mediated by P/Q-type high voltage activated Ca++ channels. In slices, LY341495 (a group-II mGlu receptor antagonist) enhanced the NMDA-induced ACh release, suggesting that group-II mGlu receptor activation by endogenous glutamate inhibits NMDA transmission. Co-immunoprecipitation studies excluded direct group-II mGlu-NMDA receptor interactions. Finally, group-II mGlu negative modulation of NMDA transmission was abolished in dopamine-depleted synaptosomes and slices, suggesting that it relied on endogenous dopamine. We conclude that group-II mGlu receptors attenuate NMDA inputs at striatal cholinergic terminals via Ca++ channel modulation and dopamine-sensitive pathways.
Mela
Flora
F
Section of Pharmacology, and Neuroscience Center, Department of Experimental and Clinical Medicine, University of Ferrara, via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
Marti
Matteo
M
Fiorentini
Chiara
C
Missale
Cristina
C
Morari
Michele
M
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020865:Calcium Channels, P-Type / Q000378:metabolism*; D020907:Calcium Channels, Q-Type / Q000378:metabolism*; D002794:Choline / Q000737:chemistry / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism*; D011042:Poisons / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism; D020867:omega-Agatoxin IVA / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D002121:Calcium Channel Blockers; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018690:Excitatory Amino Acid Agonists; D011042:Poisons; D021122:Protein Subunits; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C108822:metabotropic glutamate receptor 2; D020867:omega-Agatoxin IVA; D014316:Tritium; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D002794:Choline; D000109:Acetylcholine; C104753:eglumetad; D011188:Potassium; D004298:Dopamine