Associate editor: T.C. Napier
Neurobiology of relapse to alcohol in rats

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Abstract

Relapse to alcohol use after prolonged withdrawal periods is the major problem in the treatment of alcohol dependence in humans. However, until recently, relatively few preclinical studies concentrated on the elucidation of the neurochemical events underlying relapse to alcohol. In this article we will review recent data from studies in which alcohol-deprivation and reinstatement models were used to determine the mechanisms underlying relapse to alcohol in rats. In the alcohol-deprivation model, the intake of alcohol is determined after prolonged periods of forced abstinence in drug-experienced rats. In the reinstatement model, the ability of acute non-contingent exposure to drug or non-drug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies, which used these preclinical models, on the effect of specific pharmacological agents on relapse to alcohol seeking induced by re-exposure to alcohol and to alcohol-associated cues and by exposure to stress. Subsequently, we will describe potential neuronal circuits that may underlie relapse to alcohol. Finally, future directions and clinical implications of the study of relapse to alcohol in laboratory animals will be discussed briefly.

Introduction

High rates of relapse to drug use after long periods of abstinence characterize the behavior of experienced users of alcohol and other drugs of abuse Hunt et al., 1971, Miller, 1991, O'Brien, 1997. Clinical reports and laboratory studies in humans have identified a number of factors that provoke alcohol relapse and craving in humans (Larimer et al., 1999). These include acute re-exposure to alcohol or alcohol priming Chutuape et al., 1994, Hodgson et al., 1979, Ludwig et al., 1974, exposure to environmental stimuli previously paired with alcohol or conditioned alcohol cues Monti et al., 1993, Staiger & White, 1991, White & Staiger, 1991, and exposure to environmental stressors Brown et al., 1995, Cooper et al., 1992, Hore, 1971.

In the last several decades, most basic research using animal models has concentrated on the initiation and maintenance phases of alcohol intake (Samson & Harris, 1992) and on the behavioral and physiological effects of withdrawal from alcohol Becker, 2000, Myrick et al., 2001. The early literature on alcohol consumption in rats and mice has faced much controversy because it has been argued that the pattern of alcohol consumption in these species does not produce blood alcohol concentrations that mimic intoxication in humans Cicero et al., 1980, Holloway et al., 1984. However, this issue is currently rarely debated due to the development of a number of experimental approaches wherein rodents consume large amounts of alcohol in short periods of time, leading to high levels of blood alcohol. These approaches include the breeding of lines of rats that have been selectively bred for high and low alcohol consumption (Li et al., 1993), the establishment of the sucrose-fading procedure to initiate operant alcohol self-administration (Grant & Samson, 1985), and the development of limited-access intermittent drinking procedures Amit et al., 1976, Linseman, 1987.

While relapse is the major clinical problem in alcohol addiction preclinical research in the alcohol area has paid little attention to this issue. This state of affair is probably due to the widely held assumption that the understanding of the neurobiological factors involved in alcohol reinforcement and dependence would lead to the development of effective pharmacotherapies for the prevention of alcohol relapse after periods of abstinence Becker, 2000, Myrick et al., 2001, Samson & Harris, 1992, Sellers et al., 1992, Spanagel & Zieglgänsberger, 1997. However, as argued by Berke and Hyman (2000), knowledge about the mechanisms underlying drug reinforcement and dependence may not be sufficient to explain why when drugs are unavailable for prolonged periods individuals remain vulnerable to relapse. Indeed, recent studies with heroin- and cocaine-trained rats suggest that the mechanisms underlying relapse induced by drug or non-drug stimuli can be dissociated from those involved in drug reinforcement and dependence Cornish & Kalivas, 2000, Grimm & See, 2000, Self et al., 1996, Shaham et al., 1996, Shaham et al., 2000.

The purpose of the present paper is to review the recent preclinical literature on relapse to alcohol. We will start by describing the two main procedures that are currently used to study relapse in the alcohol field; namely, the alcohol-deprivation and reinstatement models. We will then review studies on the effect of re-exposure to alcohol and alcohol-related cues and exposure to stress on relapse behavior in rats. We will then review studies on the effect of pharmacological agents on relapse to alcohol seeking. Subsequently, we will describe potential neuronal circuits, which may underlie relapse to alcohol. Finally, future directions and clinical implications will be briefly discussed.

Section snippets

Methods employed to study relapse to alcohol in rats

In this section, we will review data from studies in which alcohol-deprivation and reinstatement models were used to determine mechanisms underlying relapse to alcohol in rats. In the alcohol-deprivation model, the intake of alcohol is determined after prolonged periods of forced abstinence in drug-experienced rats Sinclair & Senter, 1967, Spanagel & Holter, 2000, Wolffgramm et al., 2000. In the reinstatement model, the ability of acute non-contingent exposure to drug or non-drug stimuli to

Effect of pharmacological manipulations on relapse to alcohol

In recent years, several studies investigated the effect of pharmacological agents and other experimental manipulations [i.e., adrenalectomy (ADX)] on the ADE and on reinstatement of alcohol seeking by alcohol priming, alcohol cues, and foot-shock stress. The following sections review these studies, and Table 3, Table 4 summarize the main findings from these studies.

Brain mechanisms of relapse to alcohol

In Section 3, we reviewed data on the effect of pharmacological manipulations on relapse to alcohol induced by drug re-exposure, alcohol cues, and stress. An important question that is only beginning to be addressed is, what are the brain sites and circuits involved in relapse to alcohol? Here, we will speculate on the neuronal mechanisms underlying alcohol relapse.

Concluding remarks and future directions

The study of relapse to alcohol in preclinical models is a relatively new line of research. Consequently, much has yet to be learned about the processes involved. We have reviewed recent preclinical findings on relapse to alcohol-taking behavior in studies in which the alcohol-deprivation and the reinstatement models were used. The alcohol-deprivation model appears to provide a suitable method to study the impact of alcohol re-exposure on relapse. The ADE is reliably observed in both

Acknowledgements

This review was supported in part by a grant from the Ontario Mental Health Foundation. The authors contributed equally to this paper.

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