Interactions of allosteric modulators of AMPA/kainate receptors on spreading depression in the chicken retina.
The functional role of AMPA and kainate receptors in spreading depression (SD) was investigated in the isolated chicken retina. Competitive (NBQX) and non-competitive (GYKI 52466, GYKI 53405 and GYKI 53655) antagonists of the AMPA receptor inhibited AMPA-induced SD in a concentration-dependent manner. Concentrations of drugs caused 50% inhibition (IC(50) values) are 0.2, 16.6, 7.0 and 1.4 microM, respectively. AMPA receptor positive modulator cyclothiazide was more effective in the potentiation of SD evoked by AMPA than by kainate. Slight potentiation of either AMPA- or kainate-induced SD was observed only at high concentration (1 mg/ml) by the kainate receptor modulator concanavalin A. Compounds that positively modulate AMPA receptor function (cyclothiazide, IDRA-21, S 18986, 1-BCP and aniracetam) caused a concentration-dependent potentiation in SD. Concentrations of drugs that caused 50% potentiation (estimated EC(50) values) are 9, 135, 142, 450 and 1383 microM, respectively. Interaction between cyclothiazide, aniracetam or S 18986 administered with each other, or with GYKI 52466, respectively, was also investigated. When cyclothiazide and S 18986 were co-applied, their effects seemed to be additive. However, lack of additivity was obtained when S 18986 was added together with aniracetam. Positive modulators applied at equiactive concentrations reduced the inhibitory action of GYKI 52466 and differently shifted its concentration-response curve. In this respect, S 18986 was the most effective (IC(50) of GYKI 52466 changed from 16.6 to 51.9 microM). Our findings indicate the contribution of AMPA rather than kainate receptors in the mediation of retinal spreading depression. Our data further support the idea that multiple positive modulatory sites are present on the AMPA receptor complex in addition to a negative modulatory site.
EGIS Pharmaceuticals Ltd., Division of Preclinical Research, CNS Pharmacology, H-1475 Budapest 10, P.O. Box 100, Hungary.
Szabolcs
S
Kertész
Gábor
G
Kapus
György
G
Lévay
D000495:Allosteric Site / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001581:Benzothiadiazines / Q000378:metabolism / Q000494:pharmacology; D002645:Chickens; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D018091:Receptors, AMPA / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000378:metabolism*
D001581:Benzothiadiazines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors