Vol. 302, Issue 3, 1193-1200, September 2002

Ethanol Suppresses Fast Potentiation of Glycine Currents by Glutamate

Li Zhu, Kresimir Krnjevi, Zhenghlin Jiang, Joseph J. McArdle and Jiang Hong Ye

Departments of Anesthesiology and Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey (L.Z., Z.L.J., J.J.M., J.H.Y.), and Anaesthesia Research, McGill University, Montreal, Quebec, Canada (K.K.)

Excitatory (glutamate) and inhibitory (GABA_A and glycine) receptor/channels coexist in many neurons. To assess effects of ethanol on the interaction of glutamate and glycine receptors, glycine-induced current (I_Gly) was recorded by a whole-cell patch-clamp technique from neurons freshly dissociated from the ventral tegmental area of rats. A conditioning prepulse of glutamate (1-3 s, 1 mM) significantly and reversibly potentiated responses to a pulse of glycine. This potentiation was increased when extracellular calcium was raised to 12 mM and reduced by including 10 mM 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid in the internal recording medium. It was not affected by 5 µM 1-N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62), a selective inhibitor of calcium/calmodulin-dependent protein kinase II. In a concentration-response analysis, a conditioning pulse of glutamate significantly lowered the EC₅₀ for glycine and increased the maximal I_Gly. Kinetic analysis of the currents indicated that glutamate slowed deactivation of glycine-gated chloride channels; therefore, glutamate may increase the affinity of glycine receptors for glycine. When coapplied with glycine, ethanol (10 mM) potentiated I_Gly in 35% of neurons from the ventral tegmental area. In contrast, when coapplied with glutamate and glycine, ethanol suppressed the glutamate-induced potentiation of I_Gly in these neurons. This suppression was also observed when ethanol and glycine were coapplied after a glutamate prepulse. A similar effect was observed when ethanol alone did not potentiate I_Gly. These findings suggest that glutamate-induced calcium influx modulates glycine receptors by a mechanism that can be blocked by ethanol.