Pharmacological heterogeneity of release-regulating presynaptic AMPA/kainate receptors in the rat brain: study with receptor antagonists.
Presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptors mediating hippocampal [(3)H]noradrenaline or [(3)H]serotonin release, striatal [(3)H]dopamine release and cortical [(3)H]acetylcholine release were pharmacologically characterized using several AMPA/kainate receptor antagonists. The releases of the four transmitters elicited by exposing synaptosomes to AMPA were antagonized by NBQX, indicating that they reflect AMPA/kainate receptor activation. GYKI52466 did not inhibit the AMPA-induced release of [(3)H]noradrenaline, [(3)H]dopamine or [(3)H]serotonin, while it weakly affected the AMPA-mediated release of [(3)H]acetylcholine. On the contrary, LY300164 and LY303070 were potent antagonists able to discriminate among AMPA/kainate receptor subtypes. Both compounds blocked the AMPA receptors mediating [(3)H]dopamine and [(3)H]acetylcholine release. However, LY303070, but not LY300164, inhibited the AMPA-induced release of [(3)H]noradrenaline, while the AMPA-mediated [(3)H]serotonin release was sensitive to LY300164 but not to LY303070. SYM2206 mimicked LY300164 and prevented the AMPA-induced release of [(3)H]dopamine, [(3)H]acetylcholine and [(3)H]serotonin, but not that of [(3)H]noradrenaline. NS102 failed to antagonize the AMPA-induced release of all four transmitters. LY293558 prevented the AMPA-mediated release of [(3)H]noradrenaline, [(3)H]dopamine, [(3)H]acetylcholine or [(3)H]serotonin. Differently, LY377770 did not inhibit the AMPA-mediated release of [(3)H]noradrenaline and [(3)H]acetylcholine, but it potently blocked the AMPA-induced release of [(3)H]serotonin and, less so, of [(3)H]dopamine. AMOA inhibited the AMPA-induced release of [(3)H]serotonin or [(3)H]acetylcholine, but not that of [(3)H]noradrenaline or [(3)H]dopamine. GAMS prevented the AMPA-mediated release of [(3)H]acetylcholine and, more weakly, that of [(3)H]dopamine, but it failed to inhibit the release of [(3)H]noradrenaline or [(3)H]serotonin elicited by AMPA. gamma-DGG did not affect the AMPA-mediated release of any of the four transmitters studied. In conclusion, based on the antagonist profiles obtained, the four receptors here analyzed all belong to the AMPA-preferring subclass of glutamate receptors; however, they appear to differ from each other, probably due to differences in subunit composition. The compounds LY300164, LY303070, LY377770, AMOA and GAMS may be useful to discriminate among AMPA-preferring receptor subtypes.
Ghersi
Chiara
C
Sezione di Farmacologia e Tossicologia, Dipartimento di Medicina Sperimentale, Università di Genova, Italy.
Bonfanti
Andrea
A
Manzari
Benedetta
B
Feligioni
Marco
M
Raiteri
Maurizio
M
Pittaluga
Anna
A
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D017661:Receptors, Presynaptic / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000109:Acetylcholine; D004298:Dopamine; D018691:Excitatory Amino Acid Antagonists; D009638:Norepinephrine; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D017661:Receptors, Presynaptic; D012701:Serotonin