Interactions of 2,3-benzodiazepines and cyclothiazide at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices

摘要

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 μM; GYKI 53405 3.1 ±0.6 μM; GYKI 53655 0.8±0.1 μM). 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 μM) dramatically slowed desensitization of AMPA-induced currents and potentiated steady state currents (EC_(50) 10.0±2.5 μM) 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 μM; τ_(off) 31.6 ±6.6 μM). 4 Cydothiazide (10-100 μM) shifted the concentration-response curves of the 2,3-benzodiazepines to the right. For example, with 10 μM 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 μM, respectively.