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Interactions of 2,3‐benzodiazepines and cydothiazide at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices
Author(s) -
Rammes Gerhard,
Swandulla Dieter,
Collingridge Graham L.,
Hartmann Sabine,
Parsons Chris G.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb16718.x
Subject(s) - ampa receptor , chemistry , antagonist , pharmacology , glutamate receptor , biophysics , receptor , biochemistry , biology
1 The 2,3‐benzodiazepines GYKI 52466, GYKI 53405 and GYKI 53655 antagonized AMPA‐induced currents in cultured superior colliculus neurones in a non use‐dependent manner (steady state IC 50 S: GYKI 52466 9.8±0.6 μ m ; GYKI 53405 3.1±0.6 μ m ; GYKI 53655 0.8±0.1 μ m ). 2 Higher concentrations of all three antagonists slowed the onset kinetics and quickened the offset kinetics of AMPA‐induced currents indicative of an allosteric interaction with the AMPA recognition site. 3 Cydothiazide (3–300 μ m ) dramatically slowed desensitization of AMPA‐induced currents and potentiated steady state currents (EC 50 10.0±2.5 μ m ) to a much greater degree than peak currents. Both τ on and τ off were also increased by cydothiazide in a concentration‐dependent manner (EC 50 : τ on 42.1±4.5 μ m ; τ off 31.6±6.6 μ.M). 4 Cydothiazide (10–100 μ.M) shifted the concentration‐response curves of the 2,3‐benzodiazepines to the right. For example, with 10 μ m cydothiazide the IC 50 S of GYKI 52466 and GYKI 53405 on steady‐state AMPA‐induced currents were 57.9±9.5 and 41.6±1.5 μ m respectively. 5 GYKI 53405 and GYKI 52466 concentration‐dependently reversed the effects of cydothiazide (100 μ m ) on offset kinetics (GYKI 53405 IC 50 16.6±4.2 μ m ). However, the 2,3‐benzodiazepines were unable to reintroduce desensitization in the presence of cydothiazide and even concentration‐dependently slowed the onset kinetics of AMPA responses further (GYKI 53405 EC 50 8.0±2.8 μ m ). 6 GYKI 52466 decreased the peak amplitude of hippocampal area CA1 AMPA receptor‐mediated exdtatory postsynaptic currents (e.p.s.cs) (IC 50 10.8±0.8 μ m ) with no apparent effect on response kinetics. Cydothiazide prolonged the decay time constant of AMPA receptor‐mediated e.p.s.cs (EC 50 35.7±6.5 μ m ) with less pronounced effects in slowing e.p.s.c. onset kinetics and increasing e.p.s.c. amplitude. 7 Cydothiazide (330 μ m ) shifted the concentration‐response curve for the effects of GYKI 52466 on AMPA receptor‐mediated e.p.s.c. peak amplitude to the right (GYKI 52466 IC 50 26.9±9.4 μ m ). Likewise, GYKI 52466 (30–100 μ m )) shifted the concentration‐response curve for the effects of cydothiazide on AMPA receptor‐mediated e.p.s.c. decay time constants to the right. 8 In conclusion, cydothiazide and the 2,3‐benzodiazepines seem to bind to different sites on AMPA receptors but exert strong allosteric interactions with one another and with other domains such as the agonist recognition site. The interactions of GYKI 52466 and cydothiazide on AMPA receptor‐mediated e.p.s.cs in area CA1 of hippocampal slices provide evidence that the decay time constant of these synaptic events are not governed by desensitization.