REDUCTION OF GABA-A RECEPTOR-MEDIATED INHIBITION BY THE NON-NMDA RECEPTOR ANTAGONIST 6-CYANO-7-NITROQUINOXALINE-2,3-DIONE IN CULTURED NEURONS OF RAT-BRAIN

The action of the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) on gamma-aminobutyric acid-A (GABA(A)) receptor-mediated currents was studied in dissociated rat midbrain and hypothalamic cultures using whole-cell recording. Spontaneous synaptic activity consisted of excitatory (EPSCs) and inhibitory postsynaptic currents (IPSCs). Bicuculline (20-mu-M) blocked IPSCs and increased the frequency of EPSCs. CNQX (1-mu-M) reduced both EPSCs and IPSCs. In the presence of 0.3-mu-M tetrodotoxin (TTX), CNQX (1-20-mu-M) blocked evoked EPSCs and reduced IPSCs. In TTX, increasing K+ (20 mM) evoked EPSCs and IPSCs in a Ca-dependent manner. CNQX (10-mu-M) blocked evoked EPSCs and diminished evoked IPSCs similarly as miniature IPSCs. Muscimol-(0.2-5-mu-M) induced currents were dose-dependently reduced by CNQX (10-50-mu-M). It is concluded that CNQX reduces GABA(A) receptor-mediated inhibition primarily by reducing the excitatory drive in the evolving network, but, in addition, has a significant blocking effect on the GABA(A) receptor-channel complex.