Review
5-HT3 receptors and the neural actions of alcohols: an increasingly exciting topic

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Abstract

The 5-HT3 receptor is a ligand-gated ion channel activated by the neurotransmitter serotonin. Receptors of this subtype have been localized to several regions of the brain, and appear to be involved in many neuronal functions including responses to alcohol and other drugs of abuse. There is an extensive and growing literature indicating that 5-HT3 receptors are involved in several facets of alcohol seeking behavior, alcohol intoxication and addiction. In addition, there is strong evidence that alcohols, including ethanol, alter the function of the 5-HT3 receptor, possibly through actions on the receptor protein itself. In this article, our current understanding of the role of the 5-HT3 receptor in alcohol abuse and alcoholism will be reviewed. In addition, an overview of current understanding of the mechanism of alcohol actions of the receptor is provided.

Introduction

The neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) has been implicated in several aspects of brain function including regulation of affective states, ingestive behavior and addiction. Serotonin is especially strongly implicated in alcohol abuse and addiction, as has been reviewed elsewhere (Grant, 1995, Lovinger, 1997a). For the purposes of this review, I will concentrate on one aspect of the role of 5-HT in alcohol abuse, namely, the involvement of one receptor for this neurotransmitter, the 5-HT3 receptor.

Serotonin can activate a number of different receptor subtypes (at least 14 at last count). These receptors produce diverse neuronal responses, mostly through activation of G-protein-mediated signalling pathways. However, signalling through the 5-HT3 receptor stands out from other effects of 5-HT because this receptor is a member of the ligand-gated ion channel superfamily which is not linked to G-proteins. Instead, the 5-HT3 receptor contains an intrinsic ion channel that, when activated, allows cation flux through the neuronal membrane and depolarizes the membrane potential (Derkach et al., 1989, Maricq et al., 1991, Peters and Lambert, 1989). Thus, 5-HT3 receptors may be thought of as excitatory receptors. However, as we will discuss in relation to alcohol effects, the net excitatory or inhibitory effect of an agent is not solely a consequence of its effect on an individual neuron, but is more accurately judged by its actions on neuronal circuits. Thus, if a receptor acts to stimulate the activity of inhibitory neurons, then it may be viewed as having a net inhibitory effect on brain function, at least within a given brain region. I will discuss evidence that 5-HT3 receptors have such an inhibitory action.

Section snippets

5-HT3 receptors

Until very recently, the 5-HT3 receptor was thought to be formed by a single protein subunit (termed the 5-HT3RA) that was assembled in a pentameric configuration (Green et al., 1995, Maricq et al., 1991). However, recent evidence suggests that this subunit protein may assemble with subunits normally associated with the nicotinic acetylcholine receptor-channel (Van Hooft et al., 1998; but see also Fletcher et al., 1998), and with a newly discovered 5-HT3 receptor subunit (Davies et al., 1999).

Alcohol actions on the 5-HT3 receptor: possible role in intoxication

Numerous studies have documented that alcohols alter the function of 5-HT3 receptors (Barann et al., 1995, Jenkins et al., 1996, Lovinger, 1991, Lovinger and Zhou, 1993, Lovinger and Zhou, 1994, Machu and Harris, 1994; Parkier et al., 1996). The most consistent finding is that EtOH and other small to moderate chain length n-alkanols potentiate receptor function. Potentiation is also observed upon exposure to halogenated alcohols such as trichloroethanol (TCEt, the active metabolite of the

Mechanisms of alcohol action on the 5-HT3 receptor

Potentiation of 5-HT3 receptor function is associated with an apparent increase in the potency of 5-HT for receptor activation. This can be seen as a leftward shift in the 5-HT concentration-response curve. Recent studies indicate that alcohols enhance the likelihood that the channel associated with the receptor will remain in the open, ion conducting state (Zhou et al., 1998). Detailed analysis of receptor-channel kinetics indicates that alcohols favor the opening state of the channel by

Mechanism of alcohol-induced receptor inhibition

There is not a great deal of evidence indicating what mechanisms underlie alcohol inhibition of the 5-HT3 receptor. It is clear that the potency of the inhibitory actions of alcohols increases with increasing n-alkanol carbon chain length (Jenkins et al., 1996). This indicates that the site of the alcohol inhibitory action is hydrophobic. Studies of the nicotinic ACh receptor, which is part of the same molecular family as the 5-HT3R, indicate that long-chain alcohols inhibit receptor function

Molecular determinants of alcohol actions on the 5-HT3 receptor

The primary molecular site of alcohol interactions with neuronal membranes that leads to alterations in receptor function is not known. Although past investigations suggested a lipid site for alcohol actions, more recent studies have provided good evidence that alcohols and general anesthetics produce their actions through interactions with protein targets (see Franks and Lieb, 1994, for a review).

Recent studies have provided evidence consistent with the idea that alcohols interact with the 5-HT

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