Review
The persistence of maladaptive memory: Addiction, drug memories and anti-relapse treatments

https://doi.org/10.1016/j.neubiorev.2012.01.002Get rights and content

Abstract

Addiction is a chronic, relapsing disorder, characterised by the long-term propensity of addicted individuals to relapse. A major factor that obstructs the attainment of abstinence is the persistence of maladaptive drug-associated memories, which can maintain drug-seeking and taking behaviour and promote unconscious relapse of these habits. Thus, addiction can be conceptualised as a disorder of aberrant learning of the formation of strong instrumental memories linking actions to drug-seeking and taking outcomes that ultimately are expressed as persistent stimulus–response habits; of previously neutral environmental stimuli that become associated with drug highs (and/or withdrawal states) through pavlovian conditioning, and of the subsequent interactions between pavlovian and instrumental memories to influence relapse behaviour. Understanding the psychological, neurobiological and molecular basis of these drug memories may produce new methods of pro-abstinence, anti-relapse treatments for addiction.

Highlights

► Addiction is a chronic, relapsing disorder. ► Maladaptive instrumental and pavlovian memories increase the risk of relapse. ► Memories can be manipulated by disrupting reconsolidation or facilitating extinction. ► Many different drug memories form in addicted individuals. ► Different drug memories are differentially susceptible to manipulation.

Introduction

Addiction, from the Latin addicere (‘to sentence’), is a chronic, relapsing disorder that is problematic for both the individual and society. Drug addiction incurs high social and economic costs, placing major demands on policing and medical resources. In the UK, the cost of harm from Class A drug use was estimated at £15.4 billion in 2003–2004 (Gordon et al., 2006). This considerable expense would be significantly reduced by implementing successful treatment programmes; for example, it has been estimated that if all heroin addicts complied with methadone treatment, the UK government would save £3–4 billion over 5 years (Cave and Godfrey, 2006). Addiction is synonymous with the term ‘substance dependence’ in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IVR) and the International Statistical Classification of Diseases and Related Health Problems (ICD10; Table 1). Both recognise drug addiction when an individual shows loss of control over drug taking behaviour, persistence of drug-taking behaviour despite negative consequences, and high motivation to take the drug at the expense of other activities.

Addiction can be analysed and conceptualised at several levels, from the psychological to the molecular biological. This article reviews addiction with a focus on how it can be conceptualised as a disorder of maladaptive memory, considering the psychological and neural basis of addictive drug-associated memories (Sections 2 Psychological associations underlying addiction, 3 Neural circuits underlying addiction) before discussing how pharmacological manipulation of these memories could be used to treat addiction (Section 4). A major problematic aspect of addiction, both clinically and for the individual, is its chronic and relapsing nature, with the propensity to relapse persisting long after the more obvious signs of acute withdrawal have abated (Gawin and Kleber, 1992). Treatments based on the disruption of drug memory reconsolidation, or facilitated extinction of drug memories, unlike currently available therapies, would target the memories that underlie the disorder to diminish the propensity to relapse long into abstinence (Section 5).

Section snippets

Drug addiction can be viewed as the aberrant engagement of normal learning processes, leading to the formation of persistent maladaptive memories

The long-term propensity of an addict to relapse suggests that it is not solely acute drug withdrawal effects, such as those found in abstinent opiate addicts (Wikler, 1948) that maintain drug use, but rather that persistent changes in brain function occur, ultimately leading to a prolonged risk of relapse following initial detoxification. One theory of addiction (Everitt et al., 2001, Everitt and Robbins, 2005) hypothesises that the long-term propensity to relapse reflects the formation of

Neural circuits underlying addiction

Although addiction to drugs is associated with changes throughout the brain, one of the key neural systems on which drugs of abuse act is the limbic corticostriatal circuitry, which is involved in motivation, reward, learning and memory. This circuitry is conserved across species, including humans, primates and rodents. Much of the research elucidating the neural circuits underlying addiction has made use of rodent models, which have been used extensively (see Sanchis-Segura and Spanagel, 2008,

Drug memory reconsolidation: Mechanisms and implications for treatment

As discussed in Section 2, the formation of addictive drug memories reflects the usurping of the learning and plasticity processes that normally underlie the learning of associations between environmental stimuli and natural reinforcers. The consolidation of drug-associated memories and the plasticity associated with addiction has been reviewed previously (Hyman et al., 2006, Jones and Bonci, 2005, Kauer, 2004). The focus of this section will be on the neurochemical and molecular mechanisms of

Alternative treatment strategies for addiction

Understanding the psychological and neural mechanisms underlying addiction should ultimately lead to the development of treatments for the disorder. However, though they work with some success, the current therapies available for addiction – pharmacotherapy and behavioural treatments–do not target one of the major underlying causes of addiction, namely, the maladaptive associations that underlie the propensity to seek and take drug, or to relapse following abstinence. Treatments based upon the

Conclusions

Drug addiction is a complex disorder of the nervous system, with potentially a number of subtypes (Redish et al., 2008), depending upon the specific vulnerabilities of the individual and the drug of abuse. However, a most problematic aspect of treating addiction is the long-term propensity of the addict to relapse (Gawin and Kleber, 1992), and this is known to be profoundly influenced by the presentation of drug-associated, environmental conditioned stimuli (Bonson et al., 2002, Boujabit et

Acknowledgments

This work was supported by a UK Medical Research Council grant (no. 9536855) to BJE, and was conducted in the Behavioural and Clinical Neuroscience Institute, funded by a joint award from the MRC and the Wellcome Trust. Matej Macak and Brian Kelleher provided technical assistance in the collection of the data shown in Fig. 2.

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