Review
Aberrant learning and memory in addiction

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Abstract

Over the past several years, drug addiction has increasingly been accepted to be a disease of the brain as opposed to simply being due to a lack of willpower or personality flaw. Exposure to addictive substances has been shown to create enduring changes in brain structure and function that are thought to underlie the transition to addiction. Specific genetic and environmental vulnerability factors also influence the impact of drugs of abuse on the brain and can enhance the likelihood of becoming an addict. Long-lasting alterations in brain function have been found in neural circuits that are known to be responsible for normal appetitive learning and memory processes and it has been hypothesized that drugs of abuse enhance positive learning and memory about the drug while inhibiting learning about the negative consequences of drug use. Therefore, the addict’s behavior becomes increasingly directed towards obtaining and using drugs of abuse, while at the same time developing a poorer ability to stop using, even when the drug is less rewarding or interferes with functioning in other facets of life. In this review we will discuss the clinical evidence that addicted individuals have altered learning and memory and describe the possible neural substrates of this dysfunction. In addition, we will explore the pre-clinical evidence that drugs of abuse cause a progressive disorder of learning and memory, review the molecular and neurobiological changes that may underlie this disorder, determine the genetic and environmental factors that may increase vulnerability to addiction, and suggest potential strategies for treating addiction through manipulations of learning and memory.

Highlights

► We review how addiction can both result from and cause aberrant learning and memory. ► Addictive drugs cause behavioral changes in both animals and humans. ► Addictive drugs cause molecular changes in learning and memory circuits. ► Genetic and environmental factors alter learning and memory and enhance addiction. ► Addiction may be treated by manipulating learning and memory systems.

Introduction

Humans sample psychoactive substances for a variety of reasons including obtaining pleasurable feelings, relieving pain or stress, reducing anxiety, increasing energy, and enhancing sociability. Using drugs for these purposes in of themselves is not necessarily harmful to the individual or to society as a whole; rather, it is the chronic, uncontrolled use of drugs at the expense of normal activities and in spite of adverse consequences that characterizes drug addiction. Drug addiction does not occur overnight, but takes years to develop, and indeed is hypothesized to be learned. Drug use begins by learning that the substance is rewarding due to powerful interoceptive effects, thus increasing the desire to use the drug again. Over time certain cues in the environment become associated with drug use until the cues alone are sufficient to stimulate desire or craving for the drug. Learning about reward-related cues also occurs when humans learn to find food or mates, build shelters, or earn money, but drugs of abuse alter and enhance these normal learning and memory processes. In addition, drugs of abuse consumed over long periods of time cause dysfunction in neural systems mediating self-control over behavior. In other words, addictive drugs not only enhance normal learning systems involved in seeking rewards, but also inhibit the ability to control use, especially in vulnerable populations (Everitt et al., 1999, Jentsch and Taylor, 1999).

Drugs of abuse are able to usurp normal learning and memory systems through their direct pharmacological actions on multiple neurotransmitter systems. For example, when a new event occurs in the environment a dopamine signal is generated from the midbrain to both dorsal and ventral striatum that facilitates learning about this new event (Jay, 2003, Schultz, 2010). A common feature of drugs of abuse is that, despite different mechanisms of action, they all cause an increase in dopamine release in the striatum (Di Chiara, 1999, Torregrossa and Kalivas, 2008). Therefore, addictive substances create artificial learning signals that are of a greater magnitude and duration than what is observed neurochemically in response to natural events. Enhanced learning about a drug positive experience results in an increased likelihood to use the drug again. This effect is magnified each time the drug is consumed. Drugs of abuse not only increase learning about the positive effects of the drug, but they also overshadow and diminish the impact of other features of the environment resulting in increased attention toward the drug and away from normal activities.

The ability of addictive substances to alter normal glutamate transmission is another means by which drugs directly affect learning and memory processes (Kalivas, 2004). Chronic drug exposure results in long-lasting alterations in glutamate homeostatsis in the nucleus accumbens coupled with enhanced glutamatergic transmission from the prefrontal cortex upon re-exposure to the drug (LaLumiere and Kalivas, 2008, McFarland et al., 2003). Glutamatergic activity is also necessary for virtually all forms of learning, and is critical for prefrontal cortical control over decision making and impulsivity (Moghaddam et al., 1997, Stefani et al., 2003). Therefore, addictive drugs have the ability to profoundly influence learning and memory circuits. Indeed, if not for this property of drugs of abuse it is not clear if they would be able to produce addictive behavior.

The clear overlap between the neurochemical and molecular processes involved in normal learning and memory and the pharmacological actions of drugs of abuse has led many scientists to hypothesize that addiction develops, at least in part, because of aberrant learning and memory (Everitt et al., 2001, Hyman et al., 2006, Jentsch and Taylor, 1999, Kelley, 2004, Kilts, 2001, Thomas et al., 2008, White, 1996). In this review, we will focus on how drugs of abuse alter normal learning and memory and discuss how specific vulnerability factors influence the ability of abused drugs to affect learning and memory systems. We will also describe human, clinical studies that have investigated how normal learning and memory systems are affected in addicts. Finally, we will explore how studies of learning and memory have influenced the direction of current research into novel treatment strategies for addiction.

Section snippets

Behavioral effects of addictive drugs on learning and memory

While it has long been observed that strong associations develop between addictive drugs and the environmental stimuli and contexts in which they are encountered, it is increasingly appreciated that chronic drug exposure leads to long-lasting changes in the circuits underlying normal learning and memory processes. Some of the first studies demonstrating drug-induced changes in normal learning examined the effect of psychostimulants on incentive learning about reward-predictive cues. Taylor and

Molecular and physiological effects of addictive drugs on learning and memory

The ability of addictive drugs to produce enduring changes in learning about cue-reward associations and developing habits, suggest that drugs may cause long-lasting synaptic plasticity in cortico-limbic-striatal circuitry. Drugs may produce these effects via altered gene and protein expression/activity, changes in electrophysiological activity, and by modifying neural morphology. A wealth of research has clearly demonstrated that chronic use of addictive substances causes long-term changes to

Individual vulnerability to the effects of addictive drugs on learning and memory

We have identified many long-term effects of addictive drugs on basic learning and memory processes and hypothesized that these effects of drugs of abuse mediate, at least in part, the development of addiction. However, many people sample addictive substances, and some even use drugs or alcohol over many years, but only a small subset of the population progresses to addiction. Therefore, there must be environmental and/or genetic and biological factors that cause some individuals to be more

Clinical evidence for aberrant learning and memory in addiction

Despite the wealth of pre-clinical data favoring an aberrant learning and memory conception of addiction, there is a lack of clinical research exploring exactly how learning accrues to drug-predicting stimuli in human subjects. This is perhaps a result of ethical concerns with drug administration to human subjects or technical difficulties; it is difficult to know exactly what might serve as a drug-predicting cue to a human addict. There are numerous possibilities ranging from contextual cues

Developing novel treatments for addiction through manipulations of learning and memory

A preponderance of evidence suggests that the development, maintenance, and persistence of addictive behaviors, even after periods of abstinence, is dependent on the strength of drug-associated cues to motivate behavior. Therefore, research in recent years has focused on ways to reduce the ability of cues to drive drug-seeking behavior. In pre-clinical models, researchers are primarily examining the ability of treatments to prevent reinstatement, which is an animal model of clinical relapse

Summary

In conclusion, the past decade of drug addiction research has established that drugs of abuse and normal learning and memory processes produce similar molecular and neurochemical effects, suggesting that the development of addiction could be due in part to aberrant learning and memory about abused drugs. Drugs of abuse enhance learning about environmental cues associated with reinforcing events and may cause the rapid formation of habitual and ultimately compulsive behavior related to obtaining

Acknowledgments

We would like to thank the USPHS for financial support. We would also like to thank Dr. Peter Olausson for providing interesting data for our discussion.

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