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Critical assessment of how to study addiction and its treatment: Human and non-human animal models

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Abstract

Laboratory models, both animal and human, have made enormous contributions to our understanding of addiction. For addictive disorders, animal models have the great advantage of possessing both face validity and a significant degree of predictive validity, already demonstrated. Another important advantage to this field is the ability of reciprocal interplay between preclinical and clinical experiments. These models have made important contributions to the development of medications to treat addictive disorders and will likely result in even more advances in the future. Human laboratory models have gone beyond data obtained from patient histories and enabled investigators to make direct observations of human drug self-administration and test the effects of putative medications on this behavior. This review examines in detail some animal and human models that have led not only to important theories of addiction mechanisms but also to medications shown to be effective in the clinic.

Introduction

The concept of addiction as a “disease of the brain” has had an important impact, not only on the way that we think about addiction, but also on the way that it is treated. The concept implies that the brain is changed as a result of repetitive drug-taking so that when drug-taking is stopped and the drug is no longer present (detoxification), there is a strong drive toward resumption of drug-taking (reinstatement or relapse) even after months or years of abstinence from the drug. This way of looking at addiction has its roots in the observations of Abraham Wikler (1948). He documented the appearance of signs and symptoms of opiate withdrawal in addicts held in the USPHS Hospital in Lexington, KY, long after their last dose of heroin. He introduced the idea of drug withdrawal as a conditioned response and conducted studies of the phenomenon in rats whose opiate withdrawal signs were paired with environmental cues. These cues (conditioning stimuli—CS) could later elicit signs of opiate withdrawal in test animals (Wikler & Pescor, 1967). This represented an early example of an animal model that had an important impact on the treatment of addiction. The phenomenon was later produced in human volunteers in whom naloxone-precipitated opiate withdrawal signs and symptoms were paired with a novel cue (peppermint odor). After a short series of pairings, the cue (CS) was able to elicit signs and symptoms of opiate withdrawal without naloxone (O'Brien et al., 1977).

Since those early days, our understanding of the effects of drugs on the brain has continued to increase largely as a result of using laboratory models, both human and non-human animal models. Animal models of drug-taking behavior have been highly predictive of human drug preferences (Griffiths et al., 1979b). This predictability has been extremely useful in the assessment of abuse liability of potential therapeutic drugs and for the rapid testing of potential medications to be used in the treatment of addictive disorders. We now have important examples of medications that have found usefulness in the clinic after being discovered in animal models to reduce drug-seeking behavior (O'Brien, 2005).

In this review, we will examine some of the important laboratory models that have contributed to a better understanding of addiction and to the development of medications effective in treating these disorders. We will present animal models and then present the parallel human models where possible.

Section snippets

Terminology: a longstanding issue in this field

Discussions of drug addiction are often rendered confusing by a lack of clarity in distinguishing between drug dependence and drug addiction. This is often the case at the lay level; it is also far too often the case at the professional level. The term “dependence” is used in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (American Psychiatric Association [APA], 2000), the commonly used DSM-IV that constitutes the principal diagnostic manual in the field of

Addictive drug-seeking/drug-taking behavior in animals and humans

For decades, it was assumed that addictive drug-seeking and drug-taking were driven by the negative consequences of drug dependence, that is, by a desire to mitigate or avoid the unpleasant physical consequences of drug withdrawal (for review, see Gardner, 2005). This does not mean that avoidance of withdrawal is never a motivation for human addicts. Clearly, some heroin addicts in particular constantly worry about the onset of withdrawal symptoms, but the pursuit of “high” remains the goal.

Brain-reward mechanisms and addictive drug-seeking/drug-taking behavior

The reward substrates of the mammalian brain consist of an anatomically interrelated “in series” set of brain loci and interconnecting axonal projection systems (for review, see Gardner, 2005; see also Fig. 1). The system originates in an anatomically diverse group of forebrain loci labeled by some neuroanatomists (e.g., Geeraedts et al., 1990) as the “anterior bed nuclei of the medial forebrain bundle,” including the anterior lateral hypothalamus, horizontal limb of the diagonal band of Broca,

Models of physical dependence

In turning to the topic of animal models of physical dependence, it is essential to bear in mind the distinctions between physical dependence and drug addiction noted at the beginning of this review. As noted, physical dependence is the normal physiological adaptation of bodily systems to the continued presence of a drug within the body. As equally noted, drug addiction is a behavioral and mental disorder characterized by compulsive drug-seeking behavior. Also as noted, the brain loci and

Drug self-administration

Clearly, the drug self-administration model presents the most obvious and face-relevant model of addiction. Laboratory animals (ranging across mammalian species, from laboratory mouse to sub-human primate) self-administer many classes of addictive drugs, in many cases avidly. A wide range of routes of self-administration have been used in animal research on addiction—including oral, intragastric, intraperitoneal, intravenous, and intracerebral (for review, see Gardner, 2005). The oral and

Human laboratory drug administration

Much has been learned from observations of the effects of drugs of abuse given to humans in the laboratory. Some of the earliest work of this nature was conducted at the US Public Health Hospital in Lexington KY, the predecessor of the Intramural Research Program of the National Institute on Drug Abuse. The subjects were prisoners, and while they volunteered to participate in the research, the use of prisoner volunteers is not practical in the modern era. Human research committees often take

Animal models that directly probe the brain-reward substrates underlying drug addiction

At present levels of understanding, addiction is believed to be a disorder of dopamine-dependent habit formation (Di Chiara, 1999, Everitt et al., 2001, Robbins & Everitt, 2002, Wise, 2004). The dopamine dependency seems to be crucial, as dopamine appears to be essential for the “stamping in” of the response–reward and stimulus–reward associations that underlie the pathognomonic behavioral symptoms of addiction—the aberrantly strong motivational and reinforcing control over behavior by

Animal models of relapse—methods

Two basic animal model systems have been developed to model relapse to addictive drug-seeking and drug-taking behavior—the “reinstatement” model based upon self-administration (see Section 3.1) and the “reactivation” model based upon conditioned place preference (see Section 8 of this review).

Animal models as tools in the search for effective anti-addiction treatments

The development of effective anti-addiction pharmacotherapies is considered by many to be the single most pressing need in the field of addiction medicine at present (O'Brien, 1997). Animal models have considerable face validity, but to be useful in the treatment of addiction, they must also have predictive validity. Unlike medications for other mental disorders, most medications for addictive diseases grew out of animal models. In contrast, medications for disorders such as depression and

Acknowledgments

The preparation of this manuscript was supported by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health; by the Department of Veterans Affairs, Mental Illness Research, Education and Clinical Center; and by NIDA center P60-5186.

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