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

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. Non‐NMDA receptors were defined pharmacologically as predominantly the AMPA subtype, because both AMPA‐ or kainate‐activated currents were blocked by GYKI 52466, a selective AMPA receptor antagonist. The relative magnitude of potentiation of AMPA‐activated currents by 10 or 100 μ M cyclothiazide was consistent with recombinant AMPA flop‐subtype receptors. Finally, the selective kainate receptor agonist, SYM 8021, induced little current in MS/DB neurons. AMPA receptor currents when activated by kainate were sensitive to ethanol, showing inhibition of ∼5–50% when 10–300 m M ethanol and kainate were briefly co‐applied (3 s). Ethanol (100 m M ) also inhibited both the initial 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. Rapid application of 3–3000 μ M kainate activated concentration‐dependent currents in MS/DB neurons from Control and Ethanol Dependent animals that were not significantly different. Also, direct ethanol inhibition (300 m M ) of kainate‐activated currents was not reduced by ethanol dependence, suggesting a lack of functional tolerance. These results suggest that native AMPA receptors on MS/DB neurons are inhibited by pharmacologically‐relevant concentrations of ethanol. However, these receptors, unlike NMDA receptors, do not undergo adaptation with sustained ethanol exposure sufficient to induce physical dependence.British Journal of Pharmacology (2000) 129 , 87–94; doi: 10.1038/sj.bjp.0703039