Elsevier

Pharmacology & Therapeutics

Volume 111, Issue 3, September 2006, Pages 533-554
Pharmacology & Therapeutics

Associate editor: A.L. Morrow
Ethanol modulation of GABAergic transmission: The view from the slice

https://doi.org/10.1016/j.pharmthera.2005.11.002Get rights and content

Abstract

For almost three decades now, the GABAergic synapse has been the focus of intense study for its putative role in mediating many of the behavioral consequences associated with acute and chronic ethanol exposure. Although it was initially thought that ethanol interacted solely with the postsynaptic GABAA receptors that mediate the majority of fast synaptic inhibition in the mammalian central nervous system (CNS), a number of recent studies have identified novel pre- and postsynaptic mechanisms that may contribute to the acute and long-term effects of ethanol on GABAergic synaptic inhibition. These mechanisms appear to differ in a brain region specific manner and may also be influenced by a variety of endogenous neuromodulatory factors. This article provides a focused review of recent evidence, primarily from in vitro brain slice electrophysiological studies, that offers new insight into the mechanisms through which acute and chronic ethanol exposures modulate the activity of GABAergic synapses. The implications of these new mechanistic insights to our understanding of the behavioral and cognitive effects of ethanol are also discussed.

Introduction

γ-Aminobutyric acid (GABA) was first identified over three decades ago as the major inhibitory neurotransmitter in the mammalian central nervous system (CNS) (Bloom & Iversen, 1971). Almost immediately following those pioneering studies, reports began to emerge suggesting that the acute behavioral and cognitive effects of ethanol were mediated in part via an enhancement of GABAergic inhibition (e.g., Davidoff, 1973, Nestoros, 1980). In the coming years, numerous studies, employing a variety of behavioral, neurochemical, and electrophysiological approaches provided additional support for this hypothesis (for detailed, historical reviews of these studies, see Deitrich et al., 1989, Criswell & Breese, 2005).

The first mechanistic theories centered on the idea that ethanol enhanced synaptic inhibition primarily via a direct allosteric facilitation of the activity of GABAA receptors, which mediate the vast majority of fast synaptic inhibition in the mammalian CNS. These theories were based initially on observations from numerous behavioral studies, which noted that ethanol shared many of the sedative, anxiolytic, and anticonvulsant properties of drugs known to enhance GABAA receptor function (e.g., benzodiazepines [BZPs] and barbiturates; Deitrich et al., 1989) and that cross-tolerance could develop between ethanol and drugs that enhance GABAA receptor activity (Le et al., 1986, Mihic et al., 1992). Moreover, GABAA receptor agonists or drugs that raise endogenous levels of GABA were shown to potentiate the sedative, hypnotic, ataxic, and anticonvulsant actions of ethanol (Hakkinen & Kulonen, 1976, Frye & Breese, 1982, Liljequist & Engel, 1982, Martz et al., 1983), whereas GABAA receptor antagonists and certain benzodiazepine partial inverse agonists (Ro 45-1513) could reduce some of the intoxicating effects of ethanol (Hakkinen & Kulonen, 1976, Liljequist & Engel, 1982, Martz et al., 1983, Suzdak et al., 1986b). The findings that a range of allosteric GABAA receptor modulators could substitute for ethanol in drug discrimination studies (Kline & Young, 1986, Barry, 1991, Ator et al., 1993, Hodge & Alken, 1996) provided further support for this theory.

While the evidence from most behavioral studies supported the idea that ethanol enhanced GABAergic inhibition via an allosteric facilitation of GABAA receptor function, direct biochemical and/or electrophysiological evidence in support of such a mechanism proved surprisingly elusive. Although initial neurochemical (Suzdak et al., 1986a, Morrow et al., 1988) and electrophysiological (Aguayo, 1990, Reynolds & Prasad, 1991) studies seemed to suggest that pharmacologically relevant concentrations of ethanol could exert an allosteric facilitation of GABAA receptor function, these effects were often quite variable (Reynolds et al., 1992) and in some cases not observed (Osmanovic & Shefner, 1990, White et al., 1990, Mihic et al., 1991). Notably, evidence from in vitro studies investigating ethanol effects on GABAergic synaptic transmission also proved highly variable (see Section 3).

Over the last decade or so, a variety of methodological advances have greatly facilitated the study of the physiological and pharmacological properties of synapses in in vitro brain slice preparations. Numerous ethanol researchers have employed these improved methods to reexamine the acute effects of ethanol on GABAergic neurotransmission in a number of brain regions and in a variety of species from mouse to monkey. These recent studies have shed new light on the complexity surrounding the interaction between ethanol and the GABAergic synapse. While the majority of these studies have now provided compelling evidence that ethanol can indeed enhance GABAergic synaptic activity, these studies also suggest that the mechanisms underlying this enhancement are far more complex than initially appreciated and often involve interplay between both pre- and postsynaptic mechanisms.

The purpose of this article is to provide a highly focused overview of the findings of studies from the past decade or so that offer novel insight into specific pre- and postsynaptic mechanisms through which ethanol enhances GABAergic neurotransmission in the mammalian CNS. The focus will be mainly to examine this interaction from the perspective of native receptors in tissue slices with an emphasis on electrophysiological studies. The implications of these new mechanistic insights to our understanding of the behavioral and cognitive effects of ethanol and the treatment of alcohol-related disorders will also be discussed. Other aspects regarding the interaction of ethanol with GABAergic transmission and GABA receptors have been reviewed elsewhere (Macdonald, 1995, Klein & Harris, 1996, Mihic, 1999, Aguayo et al., 2002, Boehm et al., 2004, Kumar et al., 2004, Criswell & Breese, 2005).

Section snippets

The GABAergic synapse

As noted in Section 1, GABA serves as the primary inhibitory neurotransmitter in the mammalian CNS (Bloom & Iversen, 1971). This neutral amino acid interacts with 2 classes of ionotropic receptors (GABAA and GABAC) and 1 class of metabotropic receptor (GABAB) to limit and shape synaptic communication throughout the central nervous system (McKernan & Whiting, 1996, Krnjevic, 1997).

Acute effects of ethanol on evoked GABAergic synaptic transmission

In the early 1980s, as the importance of GABAergic neurotransmission as the major inhibitory element in the mammalian CNS became more widely appreciated, several brain slice electrophysiology laboratories began to examine the acute effects of ethanol on the inhibitory component of synaptic transmission. Most of these original studies employed sharp electrode current clamp methods to study the effects of ethanol on electrically evoked compound synaptic potentials that contained both excitatory

Synaptic mechanisms of ethanol action

From the preceding review, it is evident that pharmacologically relevant concentrations of ethanol can potentiate evoked GABAergic neurotransmission in a number of different brain regions in rodent and non-human primate brain slice preparations. In addition, there is emerging evidence that the effects of ethanol on GABAergic synapses may indeed be related to some of the acute behavioral consequences associated with ethanol exposure.

As a result of these studies, attention has turned away from

GABAB receptors

As noted earlier, Wan et al. (1996) were the first to report that blockade of metabotropic GABAB receptors enhances ethanol potentiation of evoked GABAA IPSCs in rat hippocampal CA1 pyramidal neurons. Since then, several other reports have also noted that blockade of GABAB receptors facilitates the detection of ethanol's potentiating effects on GABAergic synapses in the hippocampus (Kang et al., 1998b, Wu et al., 2005) and nucleus accumbens (Siggins et al., 1999). These findings suggest that

Effects of chronic ethanol on GABAergic synaptic transmission

From the preceding review, it is becoming increasingly clear that acute ethanol exposure has complex effects on pre- and postsynaptic elements of GABAergic synapses. Collectively, these synaptic actions of ethanol lead to an enhancement of GABAergic inhibition. Many investigators have also examined the long-term consequences of ethanol exposure on GABAergic signaling. It is well known that chronic ethanol consumption can lead to tolerance and physical dependence (Chandler et al., 1998) and that

Developmental implications

Exposure to ethanol can have devastating effects on the developing brain that persist into adulthood. Neuropsychological studies have demonstrated that fetal ethanol exposure leads to deficits in learning and memory, and animal and human studies suggest that this is due, in part, to permanent damage of the hippocampal formation (Berman & Hannigan, 2000, Bonthius et al., 2001a, Bonthius et al., 2001b, Culmsee et al., 2001, Hamilton et al., 2003). However, the mechanism(s) through which

Conclusions

Collectively, the results of the studies described in this review provide compelling evidence that pharmacologically relevant concentrations of ethanol (< 100 mM) significantly potentiate GABAergic synaptic transmission in a number of brain regions. As summarized in Fig. 1, many of these recent studies have shown that acute ethanol exposure can result in a significant modulation of GABA release. Depending on the brain region or even the type of synapse examined, this presynaptic effect may be

Acknowledgments

This work was supported by NIH grants AA13960, AA11997, AA10422 (JLW) and AA14973, and AA15614 (CFV).

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