Selective excitatory actions of DNQX and CNQX in rat thalamic neurons

The thalamic reticular nucleus (TRN) consists of GABA-containing neurons that form reciprocal synaptic connections with thalamic relay nuclei. Excitatory synaptic innervation of TRN neurons arises from glutamatergic afferents from thalamocortical relay neurons and deep layer corticothalamic neurons, and they produce excitation via both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Quinoxaline derivatives [e.g., 6,7-dinitroquinoxaline-2,3-dione (DNQX), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] have routinely been used as non-NMDA receptor antagonists over the last two decades. In this study, we examined whether quinoxaline derivatives alter the intrinsic properties of thalamic neurons in light of recent findings indicating that these compounds can alter neuronal excitability in hippocampal and cerebellar neurons via transmembrane AMPA Receptor (AMPAR) regulatory proteins (TARPs). Whole cell recordings were obtained from TRN and ventrobasal (VB) thalamic relay neurons in vitro. DNQX and CNQX produced a consistent depolarization in all TRN neurons tested. The depolarization persisted in tetrodotoxin and low Ca²+/high Mg²+ conditions, suggesting a postsynaptic site of action. In contrast, DNQX and CNQX produced little or no change in VB thalamocortical relay neurons. The nonspecific ionotropic glutamate receptor antagonist, kynurenic acid, and the selective AMPAR antagonist, 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride, blocked the DNQX-mediated depolarizations. Our results indicate that the DNQX- and CNQX-mediated depolarizations are mediated by AMPAR but not kainate receptors in TRN neurons. The AMPAR-positive allosteric modulator, trichloromethiazide, potentiated the DNQX-mediated depolarization in TRN neurons but did not unmask any excitatory actions of DNQX/CNQX in relay neurons. This selective action may not only reveal a differential TARP distribution among thalamic neurons but also may provide insight into distinct characteristics of AMPA receptors of thalamic neurons that could be exploited by future pharmacological development. Furthermore, these data suggest that quinoxaline derivatives could modulate synaptic transmission and alter neuronal excitability.