omega-agatoxin-iva and eglumetad

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.

Topics: Acetylcholine; Animals; Bridged Bicyclo Compounds; Calcium Channel Blockers; Calcium Channels, P-Type; Calcium Channels, Q-Type; Choline; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; In Vitro Techniques; Male; N-Methylaspartate; omega-Agatoxin IVA; Poisons; Potassium; Protein Subunits; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptic Transmission; Synaptosomes; Tetrodotoxin; Tritium