Associate editor: T.C. NapierNeurobiology of relapse to alcohol in rats
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.
References (204)
- et al.
Development of short-lasting alcohol deprivation effect in sardinian alcohol-preferring rats
Alcohol
(2000) - et al.
Alteration of ethanol self-administration by naltrexone
Life Sci
(1980) - et al.
The role of physical dependence in animal models of human alcoholism
Drug Alcohol Depend
(1976) - et al.
Effects of inescapable shock and shock-produced conflict on self-selection of alcohol in rats
Pharmacol Biochem Behav
(1974) - et al.
Behavioral pharmacology of cocaine and the determinants of abuse liability
- et al.
Addiction, dopamine, and the molecular mechanisms of memory
Neuron
(2000) - et al.
Ethanol-reinforced behaviour in the rat: effects of naltrexone
Eur J Pharmacol
(1999) - et al.
The role of drug-paired stimuli in extinction and reinstatement of ethanol-seeking behaviour in the rat
Eur J Pharmacol
(1999) - et al.
Reinstatement of ethanol seeking in rats: behavioral analysis
Pharmacol Biochem Behav
(2000) - et al.
Current advances and trends in the treatment of depression
Trends Pharmacol Sci
(1994)
Relationship of stress to brain and serotonin and 5-hydroxyindoleacetic acid
J Psychiatry Res
A homotaurine derivative reduces the voluntary intake of ethanol by rats: are cerebral GABA receptors involved?
Pharmacol Biochem Behav
Sources of relapse after extinction in Pavlovian and instrumental learning
Clin Psychol Rev
Differential inhibitory effects of a 5-HT3 antagonist on drug-induced stimulation of dopamine release
Eur J Pharmacol
A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior
Neuroscience
Physiological and behavioral responses to corticotropin-releasing factor: is CRF a mediator of anxiety or stress responses?
Brain Res Rev
Involvement of corticosterone in the modulation of ethanol consumption in the rat
Alcohol
Metyrapone-induced suppression of corticosterone synthesis reduces ethanol consumption in high-preferring rats
Pharmacol Biochem Behav
Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference
Pharmacol Biochem Behav
Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis
Life Sci
A neuroendocrine role in cocaine reinforcement
Psychoneuroendocrinology
Oral self administration of ethanol in free feeding rats
Alcohol
Role of serotonin and catecholaines in brain in the feeding suppressant effect of fluoxetine
Neuropharmacology
Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse
Neuropsychopharmacology
Chronic acamprosate eliminates the alcohol deprivation effect while having limited effects on baseline responding for ethanol in rats
Neuropsychopharmacology
Effect of drug influencing 5-HT function on ethanol drinking and feeding behavior in rats: studies using a drinkometer system
Neurosci Biobehav Rev
Revitalization of the AA and ANA rat lines: effects on some line characteristics
Alcohol
Effect of the 5-HT1a receptor agonist on the release of 5-HT in dorsal and median raphe-inneverated rat brain regions as measured by in vivo microdialysis
Life Sci
Specific decreases in ethanol- but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205-930
Alcohol
Alcohol dependence and the priming effect
Behav Res Ther
The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety
J Psychiatry Res
Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis
Neurosci Biobehav Rev
Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat
Neuropsychopharmacology
Regional differences in the effects of forced swimming on extracellular levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid
Brain Res
The effects of different stressors on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid
Brain Res
Zacopride, a 5-HT3 receptor antagonist, reduces voluntary ethanol consumption in rats
Pharmacol Biochem Behav
A role for corticotropin releasing factor and urocortin in behavioral responses to stressors
Brain Res
The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction
Cocaine- but not food-seeking behavior is reinstated by stress after extinction
Psychopharmacology
Serotonin uptake inhibitors: effects on motivated consummatory behaviors
J Clin Psychiatry
Naloxone retards the expression of a genetic predisposition toward alcohol drinking
Psychopharmacology
Animal models of alcohol withdrawal
Alcohol Res Health
Neurobiology of corticotropin releasing factor (CRF) receptors and CRF-binding protein: implications for the treatment of CNS disorders
Mol Psychiatry
Stress, vulnerability and adult alcohol relapse
J Stud Alcohol
Stress reinstates nicotine seeking but not sucrose solution seeking in rats
Psychopharmacology
Effects of voluntary short-term abstinence from alcohol on subsequent drinking patterns of college students
J Stud Alcohol
Learning
Synthesis and oral efficacy of a 4-(butylethylamino)pyrrolo[2,3-d]pyrimidine: a centrally active corticotropin-releasing factor1 receptor antagonist
J Med Chem
Resumption of ethanol-seeking behaviour in rats
Behav Pharmacol
United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol
Alcohol Alcohol
Cited by (207)
Relapse after electric barrier-induced voluntary abstinence: A review
2024, Current Opinion in NeurobiologyDrug priming
2021, Encyclopedia of Behavioral Neuroscience: Second EditionAlcohol: Neurobiology of Addiction
2021, Alcohol: Neurobiology of Addiction