Elsevier

Neuroscience

Volume 136, Issue 2, 2005, Pages 509-517
Neuroscience

Neuropharmacology
Acute effects of ethanol on hippocampal long-term potentiation and long-term depression are mediated by different mechanisms

https://doi.org/10.1016/j.neuroscience.2005.08.002Get rights and content

Abstract

To determine potential mechanisms contributing to ethanol-induced cognitive impairment, we examined acute effects of ethanol on hippocampal N-methyl-d-aspartate receptors and forms of synaptic plasticity thought to underlie memory processing. In the CA1 region of rat hippocampal slices, ethanol partially inhibited N-methyl-d-aspartate receptor-mediated synaptic responses at concentrations up to 180mM. The block of synaptic N-methyl-d-aspartate receptors by 60mM ethanol occluded the effects of 10μM ifenprodil, an agent that has relative selectivity for N-methyl-d-aspartate receptors expressing NR1 and NR2B subunits. Ethanol did not occlude the effects of a low concentration of 2-amino-5-phosphonovalerate, an antagonist with less N-methyl-d-aspartate receptor subtype selectivity. Recent studies indicate that ifenprodil and other NR2B-selective antagonists inhibit N-methyl-d-aspartate receptor-dependent long-term depression but not long-term potentiation. We found that ethanol reversibly inhibited long-term depression in a manner consistent with its effects on synaptic N-methyl-d-aspartate receptors. Ethanol also inhibited the induction of N-methyl-d-aspartate receptor-dependent long-term potentiation, but the actions on long-term potentiation were complex and largely irreversible over the time course of our experiments. Furthermore, ethanol inhibited a form of long-term potentiation induced by very high frequency stimulation that does not depend on N-methyl-d-aspartate receptor activation. The effects of ethanol on both forms of long-term potentiation, but not on long-term depression, were at least partially reversed by block of GABA type A receptors with picrotoxin. These results indicate that pharmacologically relevant concentrations of ethanol exert preferential effects on a subtype of synaptic N-methyl-d-aspartate receptors in the CA1 hippocampal region. Inhibition of synaptic N-methyl-d-aspartate receptors appears to contribute strongly to ethanol-mediated long-term depression inhibition, but effects on long-term potentiation are complex, involving, at least partially, changes in GABAergic transmission.

Section snippets

Hippocampal slice physiology

Hippocampal slices were prepared from P30–32 Sprague–Dawley rats using standard methods (Zorumski et al., 1996). Rats were anesthetized with halothane and decapitated. Hippocampi were rapidly dissected and placed in artificial cerebrospinal fluid (ACSF) containing (in mM): 124 NaCl, 5 KCl, 2 MgSO4, 2 CaCl2, 1.25 NaH2PO4, 22 NaHCO3, 10 glucose, bubbled with 95% O2–5% CO2 at 4–6°C, and cut transversely into 450μm slices using a vibrotome. Acutely prepared slices were placed in an incubation

Acute effects of ethanol on synaptic NMDARs

In initial experiments, we examined the effects of acute ethanol treatment on synaptic NMDARs in the CA1 region using low frequency activation of the Schaffer collateral pathway. When perfused for 10–15 min, ethanol inhibited synaptic NMDARs in a concentration-dependent fashion (Fig. 1A). At concentrations as high as 180mM, the block of NMDARs remained incomplete (67±10% inhibition, N=3). The effects of ethanol at concentrations up to 60mM were readily reversible following ethanol washout. At

Discussion

Ethanol is a non-competitive NMDAR antagonist that can inhibit the induction of NMDAR-dependent forms of LTP in the CA1 region of the hippocampus (see Allgaier 2002, Chandler 2003 for reviews). While NMDAR antagonism and LTP inhibition are thought to be related, there is evidence that ethanol’s actions on synaptic plasticity may be more complex than NMDAR inhibition (Schummers et al 1997, Schummers and Browning 2001). In our studies, we found that ethanol is a partial inhibitor of

Acknowledgments

This work was supported in part by NIH grants AA12951, AG 184334 and MH45493, and the Bantly Foundation.

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