Sustained ethanol inhibition of native AMPA receptors on medial septum/diagonal band (MS/DB) neurons

1 The direct impact of ethanol on native, non-NMDA glutamate receptors was examined in acutely isolated MS/DB neurons from rat. The impact of ethanol functional tolerance and physical dependence on non-NMDA receptor function was also determined. 2 Non-NMDA receptors were defined pharmacologically as predominantly the AM PA subtype, because both AMPA- or kainate-activated currents were blocked b y GYKI 52466, a selective AMPA receptor antagonist. The relative magnitude of potentiation of AMPA-activated currents by 10 or 100 mu M cyclothiazide was consistent with recombinant AMPA flop-subtype receptors. Finally, the s elective kainate receptor agonist, SYM 8021, induced little current in MS/D B neurons. 3 AMPA receptor currents when activated by kainate were sensitive to ethano l, showing inhibition of similar to 5-50% when 10-300 mM ethanol and kainat e were briefly co-applied (3 s). Ethanol (100 mM) also inhibited both the i nitial transient peak and sustained currents activated by AMPA. Inhibition was sustained during continuous ethanol superfusions of 5 min, suggesting a lack of acute tolerance to ethanol-induced AMPA receptor blockade. 4 Rapid application of 3-3000 mu M kainate activated concentration-dependen t currents in MS/DB neurons from Control and Ethanol Dependent animals that were not significantly different. Also, direct ethanol inhibition (300 mM) of kainate-activated currents was not reduced by ethanol dependence, sugge sting a lack of functional tolerance. 5 These results suggest that native AMPA receptors on MS/DB neurons are inh ibited by pharmacologically-relevant concentrations of ethanol. However, th ese receptors, unlike NMDA receptors, do not undergo adaptation with sustai ned ethanol exposure sufficient to induce physical dependence.