Ethanol Suppresses Fast Potentiation of Glycine Currents by Glutamate

Abstract

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, glycineinduced 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,NЈ,NЈ-tetraacetic acid in the internal recording medium. It was not affected by 5 (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 EC 50 for glycine and increased the maximal I Gly . Kinetic analysis of the currents indicated that glutamate slowed deactivation of glycinegated 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.

Effects of Ethanol on GABAA Receptors in GABAergic and Glutamatergic Presynaptic Nerve Terminals

“…We also show in the current study that EtOH concentration-dependently inhibited the response to bath application of glutamate in hippocampal CA3 pyramidal neurons. The results agree with a large number of previous reports, including in cultured rat hippocampal neurons (Lovinger et al, 1989;Weight et al, 1992), mechanically isolated rat ventral tegmental area neurons (Zhu et al, 2002), and cultured rat cerebral cortex nonpyramidal neurons (Fischer et al, 2003). The inhibitory effects of 30 and 100 mM EtOH were much greater for the extrasynaptic glutamate receptor responses, compared with the extrasynaptic GABA A receptor-mediated muscimol responses.…”

“…In cultured cell or isolated nerve cells, EtOH acts on extrasynaptic GABA A receptors to potentiate GABA-induced Cl Ϫ currents (Reynolds and Prasad, 1991;Weight et al, 1992;Aguayo et al, 1994), by increasing their open probability caused by an increase in the open time of single GABA A receptor channels (Tatebayashi et al, 1998). EtOH also acts on excitatory glutamate receptors where it has been shown to inhibit glutamate-induced currents in rat cultured hippocampal and cerebral cortex neurons (Lovinger et al, 1989;Weight at al., 1992;Fischer et al, 2003) and in rat ventral tegmental area neurons (Zhu et al, 2002). These postsynaptic effects are considered to be the major cellular mechanisms mediating the physiological effects of EtOH in reducing anxiety and causing sedation, motor impairment, cognitive impairment, and, at higher doses, amnesia and general anesthesia (Mihalek et al, 2001;Hanchar et al, 2005).…”

The free fatty acid metabolome in cerebral ischemia following human mesenchymal stem cell transplantation in rats

“…Mesenchymal stem cells (MSCs) have recently been investigated as an attractive therapeutic tool for ischemic stroke and myocardial infarction [1][2][3] because of their plasticity and availability [4]. Following stroke in a rat model, MSCs have been found to ameliorate functional deficits by secreting neurotrophic factors [5,6], which reduce apoptosis and promote endogenous cellular proliferation [5,7].…”

Supraspinal and spinal effects of L‐trans‐PDC, an inhibitor of glutamate transporter, on the micturition reflex in rats

“…Glutamate acts on the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxasole propionic acid (AMPA) receptors localized on spinal motoneurons to evoke the release of acetylcholine, while glycine released as a co‐transmitter from spinal interneurons inhibits glutamate‐evoked acetylcholine release by activating the glycine receptors on motoneurons 19. A kinetic analysis has shown that glutamate deactivates glycine‐gated chloride channels and increases the affinity of glycine receptors for glycine 20. Glycine has been established as a co‐agonist of the NMDA receptor, and positive modulation of the NMDA‐mediated current by glycine has been revealed by numerous in vitro studies 21.…”