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(p. 14) Human Laboratory Models of Addiction 

(p. 14) Human Laboratory Models of Addiction
Chapter:
(p. 14) Human Laboratory Models of Addiction
Author(s):

Barbara J. Mason

and Amanda E. Higley

DOI:
10.1093/med:psych/9780199738168.003.0002
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Subscriber: null; date: 19 November 2019

Palatable food and drugs compete for similar neurotransmitter receptors. This has led to the theory that excessive food consumption may be conceptualized as an addictive behavior.1,2 Neuroimaging and animal models have demonstrated that excessive food consumption is associated with neurobiological changes in the opiate and dopaminergic systems that parallel changes caused by drugs of abuse.1,3 Many of the closest connections between food and addictive substances have been drawn between alcohol and high-fat, high-sugar foods. In addition to producing behavioral reinforcement through the same neurobiological pathway, both high-fat sweets and alcohol are frequently used to regulate emotions.4,5 Research on human eating habits has also found behavioral evidence that maps onto substance dependence criteria such as loss of control, continued use despite negative consequences, and an inability to reduce consumption of calorie-dense foods.2

Alcohol use disorders make up the most prevalent category of substance use disorders in the United States, affecting over 18 million Americans.6 The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) characterizes alcohol dependence as a maladaptive pattern of drinking leading to clinically significant impairment, as manifested by a compulsion to drink, a lack of control over the amount of alcohol consumed, and continued drinking despite knowledge of having a persistent physical or psychological problem.7 Alcoholism is a chronic relapsing disorder that has several stages that contribute to excessive drinking and dependence. Relapse, or the return to alcohol abuse following periods of abstinence, is one of the principal characteristics of dependence on alcohol. Chronic alcohol abuse has been associated with changes in stress and reward pathways that can increase vulnerability to emotional stress and alcohol craving.8 In human alcoholics, numerous symptoms that can be characterized as “negative affect” persist long after acute physical withdrawal from alcohol. Fatigue and tension have been reported to persist up to 5 weeks post withdrawal9,10; anxiety has been shown to persist up to 9 months11; and, in 20%–25% of alcoholics, symptoms of anxiety and depression have been shown to persist up to 2 years post withdrawal.11 These postacute withdrawal symptoms (protracted abstinence) tend to be affective in nature, subsyndromal, and often precede relapses.12,13

The addiction cycle can be generally conceptualized as having three components: the preoccupation/anticipation stage, the binge/intoxication stage, and the withdrawal/negative affect stage.14 The three stages interact with each other, with the withdrawal/negative affect component becoming more intense as the addictive behavior moves from impulsive to compulsive. During the withdrawal/negative affect stage, negative reinforcement mechanisms are in effect rather than positive reinforcement mechanisms. As such, individuals will often take the addictive substance to relieve emotional withdrawal states such as anxiety, irritability or dysphoria, or to self-medicate the negative affect or general malaise. Human laboratory studies provide a powerful means of exploring pharmacological treatment targets for each stage of the addiction cycle prior to the conduct of expensive, doubleblind, placebo-controlled clinical trials. Moreover, human laboratory studies can potentially identify efficacy measures for clinical trials of prospective pharmacotherapies for each stage of the addiction cycle and can be extended to investigate real-world constructs such as vulnerability to addiction, impulsivity, craving, and resistance to relapse.

For the binge intoxication phase of the addiction cycle, human laboratory models using selfadministration procedures for alcohol, cocaine, (p. 15) heroin, marijuana, and food have been established using operant procedures in which dependent participants make a behavioral response such as pressing a computer key to receive a drug or other substance.15,16 These self-administration procedures involve administering the addictive substance in the same manner in which it is abused, utilizing different schedules of reinforcement (i.e., choice procedures, fixed or progressive ratio). Impulsivity, which is an important component of the binge/intoxication phase of addiction, can also be examined in the human laboratory paradigms. Impulsivity contributes to an increased likelihood of engaging in initial drug intake, and it may provoke relapse in dependent individuals.17 Commonly used behavioral measures of impulsivity include the delayed discounting task, where participants must choose between smaller, immediate rewards over larger delayed rewards and the Stop Task,18 which is a measure of impulse control and reaction time. Importantly, acute and chronic administration of drugs of abuse produce effects on delayed discounting and behavioral inhibition that demonstrate impaired impulse control.17

Three major factors are hypothesized to contribute to relapse: priming dose of drug, drug-associated cues, and exposure to stress. Several human laboratory procedures have been developed to reflect these aspects of craving in the preoccupation/anticipation stage. A well-studied model of the drug-associated cue component of craving is the cue-reactivity paradigm. In the cue-reactivity paradigm psychological and physiological reactivity to stimuli associated with drug-taking behavior are measured. Developed initially with nicotine, craving states have been measured that are associated with presentation of cues for smoking, alcohol, and cocaine.19 Exposure to stimuli or cues associated with drug consumption produces urges to take the drug, conditioned appetitive responses, and changes in autonomic responses. These paradigms link exteroceptive cues such as the sight and smell of alcohol, with interoceptive cues such as affective mood. Exposure to alcohol cues, such as the sight and smell of alcoholic beverages, reliably increases the urge to drink alcohol, increases salivation, and increases attention to cues.20 This response set is known as cue reactivity and has been found to be more intense in alcoholics than nonalcoholics.21 Increased reactivity and urge to drink have been found when alcoholics are exposed to their usual alcoholic beverage in laboratory settings.19 A relationship has been found between the measure of reactivity and subsequent drinking, which lends support for the predictive validity of cue reactivity as an analog for clinical outcomes.20,22,23 Moreover, cue reactivity can predict treatment outcome23 and has been validated in some cases using medications that successfully treat alcoholism. For example, naltrexone, but not toprimate, blocks cue reactivity in alcohol-dependent subjects.20,24

The human laboratory model includes measures of reactivity to alcohol and affective cues as analogs of high-risk situations and that can be combined with measures of drinking, mood, and sleep under natural conditions. A real-world aspect to cue reactivity is the association between drug intake, cues in the environment, and vulnerability for addiction. Prior work has shown that subjective and physiological reactivity to the sight and smell of alcohol (i.e., exteroceptive cues) is enhanced by induction of affective states. During the with-drawal/negative affect stage of addiction, individuals are likely to take drugs to relieve the emotional withdrawal state. Individuals self-administer drugs or alcohol to self-medicate the malaise or negative affect associated with protracted abstinence. Using this information, Mason et al (2008)25 developed a novel approach to study craving in alcoholics during protracted abstinence in which non-treatmentseeking, alcohol-dependent subjects are exposed to affective stimuli that have either positive or negative valence and then are immediately exposed to a beverage cue. A key aspect of the cue-induced paradigm is exposure to alcohol cues (sight and smell of the subject’s favorite alcoholic beverage) without the opportunity for consumption. Human models of alcohol cue reactivity use a laboratory setting to re-create risk conditions for relapse similar to those experienced by alcoholics in their natural environment.26

The highly standardized human cue reactivity model (Mason et al., 2008)25 permits sensitive and systematic evaluations of effects of medications on affective states and drinking urges, alone and in combination, that have been reliably associated with drinking relapse. The presence of an alcoholic beverage is an important contributor to relapse,27 but exposure to alcohol alone does not reflect the emotional factors often associated with relapse. Relapse studies identify negative and positive affective states as the most prevalent relapse (p. 16) precipitants.27,28 Induction of negative affective states in the cue exposure laboratory has been associated with increased reactivity,22,29,30,31 and shorter time to relapse.23 Positive affective states have also been induced in the laboratory and although less effective than negative states, were associated with significantly greater urges to relapse than neutral affective states.32

Using this paradigm, Mason et al. (2008)25 exposed a sample of non-treatment-seeking alcohol-dependent subjects to affective stimuli that had positive or negative valence and then to a beverage cue, but with no opportunity to self-administer alcohol. Cue reactivity was measured using subjective measures of craving, measures of emotional reactivity, and psychophysiological measures. Both alcohol and the positive or negative valence had the expected effects on subjective and emotional reactivity. Treatment with gabapentin (a calcium channel/GABA modulator) significantly decreased subjective craving and craving that was affectively evoked and improved several measures of sleep quality. Taken together, these results suggest that affective priming, combined with alcohol cue exposure, provides a powerful means to evaluate potential pharmacotherapies for the negative affect and preoccupation/craving phase (i.e., protracted abstinence) of addiction treatment.

Self-administration of alcohol in the laboratory is a useful tool to study effects of potential pharmacotherapies for the binge/intoxication phase of addiction. In one design, subjects are presented with a tray of alcoholic drinks and are invited to consume as many of them as they like, or to receive monetary compensation for each drink they reject. Thus, the total number of drinks, or blood alcohol concentration (BAC), is the outcome measure. This type of experiment is presumably influenced by several distinct factors that may not be affected by drug, including sensitivity and tolerance to alcohol, maintenance or loss of control, taste preferences, personality traits such as impulsivity, and the kinetics of gastrointestinal absorption. A further problem with oral alcohol administration is that even after adjusting dosages for total body weight (thus minimizing the effects of sex and body morphology) and performing the ingestion with identical experimental procedures, the maximum observed BAC and the time of its occurrence after oral ingestion vary about three-fold between subjects.33 This variability complicates the interpretation of self-administration experiments because subjects ingesting the same sequence of drinks will differ substantially in their brain alcohol exposure. The impact of the many influential factors that contribute to alcohol selfadministration cannot be easily dissected; nonetheless, it is a highly valid measure with respect to the binge/intoxication phase because the dependent variable comprises the behavior under question.

Infusing the alcohol intravenously can overcome many of the problems of alcohol self-administration. Plawecki and colleagues34,35 have developed a physiologically based pharmacokinetic (PBPK) model of alcohol administration and elimination. In this paradigm, the arterial (rather than venous) BAC is controlled, which is a better representation of BAC and can be reliably measured using breath samples.36 The PBPK model calculates an individualized infusion protocol maintaining arterial BAC within 5 mg% of the target concentration. The same principle was used to achieve rapid linear changes of arterial BAC with minimal experimental variability across subjects.37 A computer-assisted self-infusion of ethanol (CASE) model has recently been developed that employs the PBPK model to achieve an identical increment in arterial BAC each time a subject chooses to self-infuse, rather than administering a fixed dose with drinking.38 An important facet of the CASE method is that subjects do not know how much alcohol they have infused or how often they are supposed to push the “drink” button. Therefore, their decisions for or against taking another “drink” are based solely on the pharmacological alcohol effects they perceive. Thus, the effects of a potential pharmacotherapy on the binge/intoxication phase of dependence may be assessed with fewer confounding factors. From a learning theory point of view, another advantage of the CASE paradigm is that the contingency between the behavior (pushing the button to receive a “drink”) and its consequences (feeling a change in alcohol effect) is closer than with oral administration for two reasons. First, each button press results in exactly the same amount of arterial BAC increase in every subject at any time throughout the experiment. Second, all these arterial BAC increments follow exactly the same kinetics (i.e., a linear increase over a preset period of time); thus, increments are achieved with much more reliability than would be possible with drinking. Therefore, CASE enables human subjects to gain more direct control over their BAC than with oral self-administration and (p. 17) makes other implications like individual preferences for specific alcoholic beverages, brands, tastes, and/or smells irrelevant.

Converging lines of evidence indicate that stress increases risk of addictive behaviors. Early life stress and childhood maltreatment, chronic cumulative adversity, major life trauma, and negative emotionality are associated with increasing levels of drug use and abuse.39 Stress and stressors have also been associated with relapse and vulnerability to relapse.40,41 Stress responses, including changes in the activities of the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic brain stress systems, affect all phases of the addiction cycle. Psychosocial stress-related behaviors also affect dopaminergic pathways.42 These findings are beginning to provide the molecular basis for how stress and cumulative adversity initiate epigenetic changes that alter the transmission of reward pathways to affect the reinforcing properties of addictive substances. Regular and chronic drug use is associated with stress-related symptoms and changes in mental state that include increased anxiety and negative emotions, changes in sleep and food intake, aggressive behaviors, alterations in attention, concentration, memory, and desire/craving for drug.43

Stress-related responses in stress-induced craving have been elicited in individuals with addiction using a model of stress-induced responsivity with an emotional imagery paradigm based on the early work of Lang and colleagues.44 Sinha and colleagues45 found that exposure to a 5-minute individualized guided imagery of each subject’s own stressful scenario elicited multiple emotions of fear, sadness, and anger when compared with a commonly used social stress task (public speaking) that elicited fear, but no sadness or anger. Additionally, individualized stress imagery resulted in significant increases in drug craving, whereas public speaking did not.45,46 Using this paradigm, drug craving with mild to moderate levels of physiological arousal and subjective distress was reliably induced in multiple groups of alcohol-, cocaine-, and opioid-dependent individuals engaged in treatment. Moreover, individuals that use greater quantity of cocaine and alcohol, and those recovering from alcohol dependence, showed greater craving and physiological responses to stressors than control counterparts (social drinkers) in this paradigm. Stress-induced cocaine craving in the laboratory could be used to accurately predict time to relapse. Similar results have been observed for subjects dependent on alcohol or nicotine.47,48

Clinical trials have consistently shown that acamprosate and naltrexone are both active agents for the treatment of alcohol dependence. However, each drug seems to work via unique mechanisms of action. Acamprosate inhibits glutamatergic receptor function and may exert its therapeutic action by decreasing an alcoholic’s “need” to drink49,50 by normalizing dysregulation in brain systems caused by chronic alcohol use and withdrawal. In contrast, naltrexone exerts its effect by blockade of opioid receptors, which are involved in alcohol’s rewarding effects on the brain.51 As a result, a patient drinking alcohol while on naltrexone is hypothesized to experience less reinforcing euphoria, resulting in less consumption (i.e., binge/intoxication), which is appropriately measured in the alcohol self-administration paradigm of the human laboratory models. Conversely, acamprosate, a glutamate modulator, is hypothesized to exert its effect by normalizing dysregulated brain stress and reward systems in early abstinence, thereby reducing risk for a return to drinking in the negative affect and preoccupation/craving phase of addiction. Therefore, acamprosate may be most appropriately studied in the cue- or stress-induced paradigms and not in those relying on alcohol administration. When using human laboratory models to screen potential pharmacotherapies for addiction, it is critical to choose the model appropriate for the mechanism of action of the drug under study to avoid false-negative findings.

When opioid receptor blockers, such as naltrexone, are used to block the reward pathway, binge eaters acutely reduce their consumption of sweet, high-fat foods,52 and alcohol-dependent participants reduce their consumption of alcohol.53 If the characterization of excessive food consumption as a possible addictive behavior is accurate, there may be important implications for the prevention and treatment of excessive food consumption. Perhaps the most important implication is the potential impact of highly available energy-dense foods and the advertising to promote its consumption. The widespread availability and aggressive advertising of unhealthy foods may play on cue-triggered relapse to derail public health interventions aimed to decrease consumption of these unhealthy foods. With respect to identifying underlying mechanisms and consequent approaches to treatment, empirically validated approaches for substance (p. 18) dependence may have comparable relevance for pathological eating. Interventions for both disorders include identification and avoidances of triggers as a relapse prevention strategy and methods to decrease the severity of a binge if relapse occurs. Studies of underlying mechanisms of obesity and potential pharmacotherapies for pathological eating should exploit the human laboratory models of cue-and stress-induced craving and self-administration described in this review to advance our understanding of the underlying mechanisms of pathological food consumption and the development of potential novel treatments.

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