Harriet de Wit

The reinstatement model of drug relapse: history, methodology and major findings

AbstractRational and objectives. The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking.Conclusions. The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.

Impulsivity as a determinant and consequence of drug use: a review of underlying processes

Impulsive behaviors are closely linked to drug use and abuse, both as contributors to use and as consequences of use. Trait impulsivity is an important determinant of drug use during development, and in adults momentary ‘state’ increases in impulsive behavior may increase the likelihood of drug use, especially in individuals attempting to abstain. Conversely, acute and chronic effects of drug use may increase impulsive behaviors, which may in turn facilitate further drug use. However, these effects depend on the behavioral measure used to assess impulsivity. This article reviews data from controlled studies investigating different measures of impulsive behaviors, including delay discounting, behavioral inhibition and a newly proposed measure of inattention. Our findings support the hypothesis that drugs of abuse alter performance across independent behavioral measures of impulsivity. The findings lay the groundwork for studying the cognitive and neurobiological substrates of impulsivity, and for future studies on the role of impulsive behavior as both facilitator and a result of drug use.

Preference for Immediate over Delayed Rewards Is Associated with Magnitude of Ventral Striatal Activity

Discounting future outcomes as a function of their deferred availability underlies much of human decision making. Discounting, or preference for immediate over delayed rewards of larger value, is often associated with impulsivity and is a risk factor for addictive disorders such as pathological gambling, cigarette smoking, and drug and alcohol abuse. The ventral striatum (VS) is involved in mediating behavioral responses and physiological states associated with reward, and dysregulation of the VS contributes to addiction, perhaps by affecting impulsive decision-making. Behavioral tests of delay discounting (DD), which index preference for smaller immediate over larger delayed rewards, covary with impulsive tendencies in humans. In the current study, we examined the relationship between individual differences in DD, measured in a behavioral assessment, and VS activity measured with blood oxygenation level-dependent functional magnetic resonance imaging, in 45 adult volunteers. VS activity was determined using a task involving positive and negative feedback with monetary reward. Analyses revealed that individual differences in DD correlate positively with magnitude of VS activation in response to both positive and negative feedback, compared with a no-feedback control condition. Variability in DD was also associated with differential VS activation in response to positive, compared with negative, feedback. Collectively, our results suggest that increased preference for smaller immediate over larger delayed rewards reflects both a relatively indiscriminate and hyper-reactive VS circuitry. They also highlight a specific neurocognitive mechanism that may contribute to increased risk for addiction.

Acute administration of d-amphetamine decreases impulsivity in healthy volunteers.

This study investigated the acute behavioral effects of d-amphetamine on several behavioral indices of impulsivity. Impulsivity has been defined, variously, as difficulty in inhibiting inappropriate behaviors, inability to wait, insensitivity to delayed consequences or an alteration in the perception of time; standardized procedures have been developed to measure these behavioral dimensions. However, it is not known how drugs affect these measures, and few studies have examined more than one measure in a single study. In this study, 36 healthy men and women participated in three sessions, in which they received placebo, 10 mg, or 20 mg d-amphetamine in randomized order. On each session they performed the following five tasks: the Stop Task, which measures behavioral inhibition, a delay discounting task, which measures the relative value of immediate vs. delayed rewards, a delay of gratification task, a Go/No-Go task, and a time estimation task. Subjects also completed mood questionnaires. Amphetamine produced its expected subjective, mood-altering effects, including increases in POMS Friendliness and Elation scales, and ARCI Euphoria and Stimulant scales. On the measures of impulsivity, amphetamine decreased impulsive responding on three of the tasks: on the Stop Task it decreased Stop reaction times without affecting Go reaction time, on the Go/No-Go task, it decreased the number of false alarms, and on the delay discounting measure, amphetamine (20 mg) decreased k values indicating less discounting of delayed reward. Other measures of impulsive behavior were unaffected. These results suggest that acute doses of amphetamine decrease several forms of impulsive behavior. These findings extend and confirm previous findings in humans and laboratory animals.

Effects of THC on Behavioral Measures of Impulsivity in Humans

This study investigated the acute effects of Δ9-tetrahydrocannabinol (THC) on four behavioral measures of impulsivity in recreational marijuana users. Although impulsive behavior has been studied using several different measures of impulsivity, few studies have utilized more than one of these measures on a single cohort. In this study, 37 healthy men and women participated in three sessions, in which they received capsules containing placebo, 7.5, or 15 mg THC in randomized order under double-blind conditions. Subjects were tested on the following four tasks: the Stop task, which measures the ability to inhibit a prepotent motor response; a Go/no-go task; a Delay discounting task, which measures the value of delayed or uncertain reinforcers; and a time estimation task, which measures alterations in time perception through a time reproduction procedure. Subjects also completed mood questionnaires and general measures of performance. THC produced its expected effects on subjective measures including increases in ARCI euphoria and marijuana scales. THC increased impulsive responding on the Stop task but did not affect performance on either the Go/no-go or Delay or Probability discounting tasks. On the time reproduction task, THC increased estimates of the duration of short intervals while not affecting estimates of longer intervals. There were no significant correlations between the four tasks either before or after drug administration. These results suggest that THC may increase certain forms of impulsive behavior while not affecting other impulsive behaviors. The dissociations between the four measures of impulsivity suggest that impulsivity is an assemblage of distinct components rather than a unitary process.

Association between A2a receptor gene polymorphisms and caffeine-induced anxiety.

The adenosine receptor system, which mediates the psychoactive effects of caffeine, is also thought to be involved in the regulation of anxiety. In this study, we examined the association between variations in anxiogenic responses to caffeine and polymorphisms in the A1 and A2a adenosine receptor genes. Healthy, infrequent caffeine users (N=94) recorded their subjective mood states following a 150 mg oral dose of caffeine freebase or placebo in a double-blind study. We found a significant association between self-reported anxiety after caffeine administration and two linked polymorphisms on the A2a receptor gene, the 1976C>T and 2592C>Tins polymorphisms. Individuals with the 1976T/T and the 2592Tins/Tins genotypes reported greater increases in anxiety after caffeine administration than the other genotypic groups. The study shows that an adenosine receptor gene polymorphism that has been associated with Panic Disorder is also associated with anxiogenic responses to an acute dose of caffeine.

GABAB receptor agonists for the treatment of drug addiction: a review of recent findings

A growing preclinical and clinical literature suggests that GABA(B) receptor agonists promote abstinence and reduce the use of cocaine, heroin, alcohol and nicotine. The purpose of this paper is to critically review these data. GABA(B) receptor agonists, such as baclofen, appear to reduce the reinforcing effects of abused drugs in animal models under multiple experimental procedures. This occurs at doses that have little effect on responding for other positive reinforcers such as food or water. We review evidence that these potential therapeutic effects may be mediated by modulation of mesolimbic dopamine neurons. This review also examines the preliminary clinical data from studies of the efficacy of baclofen for treatment of cocaine, alcohol, and nicotine dependence. We suggest that these preliminary data provide a rationale for conducting more systematic studies of the effects of GABA(B) receptor agonists as treatment for drug abuse. This line of research may also improve our understanding of the neurochemical mechanisms underlying the drug dependence process.

Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking

CONTEXT Excessive consumption of alcohol is a major problem in the United States and abroad. Despite many years of study, it is unclear why some individuals drink alcohol excessively while others do not. It has been postulated that either lower or greater acute responses to alcohol, or both, depending on the limb of the breath alcohol concentration curve, contribute to propensity for alcohol misuse. OBJECTIVE To prospectively assess the relationship of acute alcohol responses to future binge drinking. DESIGN Within-subject, double-blind, placebo-controlled, multidose laboratory alcohol challenge study with intensive follow-up. Each participant completed 3 randomized sessions examining responses to a high (0.8 g/kg) and low (0.4 g/kg) alcohol dose and placebo, followed by quarterly assessments for 2 years examining drinking behaviors and alcohol diagnoses. SETTING Participants recruited from the community. PARTICIPANTS High-risk heavy social drinkers aged 21 to 35 years who habitually engage in weekly binge drinking (n = 104) and light drinker controls (n = 86). INTERVENTION We conducted 570 laboratory sessions with a subsequent 99.1% follow-up (1506 of 1520). MAIN OUTCOME MEASURES Biphasic Alcohol Effects Scale, Drug Effects Questionnaire, cortisol response, Timeline Follow-Back, Drinker Inventory of Consequences-Recent, and DSM-IV alcohol abuse and dependence. RESULTS Alcohol produced greater stimulant and rewarding (liking and wanting) responses and lower sedative and cortisol responses in heavy vs light drinkers. Among the heavy drinkers, greater positive effects and lower sedative effects after alcohol consumption predicted increased binge drinking frequency during follow-up. In turn, greater frequency of binge drinking during follow-up was associated with greater likelihood of meeting diagnostic criteria for alcohol abuse and dependence. CONCLUSIONS The widely held low level response theory and differentiator model should be revised: in high-risk drinkers, stimulant and rewarding alcohol responses even at peak breath alcohol concentrations are important predictors of future alcohol problems. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00961792.

Behavioral and Biological Indicators of Impulsivity in the Development of Alcohol Use, Problems, and Disorders

Alcohol use disorders (AUDs) are a devastating public health problem. The construct of impulsivity is biologically based and heritable, and its various dimensions are relevant for understanding alcohol use. The goal of the current manuscript is to review recent behavioral and biological research examining various dimensions of impulsivity and their relation to AUDs from risk for initial use through dependence and relapse. Moreover, we also highlight key psychological variables including affective processes as they relate to current use and early indications of alcohol problems, as well as psychopathology, violence, and aggression in relation to AUDs. Each section includes a critical summary and we conclude the review with future directions focused on issues relevant to measurement, causality, and intervention. Throughout the review, we attempt to be as specific as possible about the dimensions of impulsivity being referenced, while attempting to draw parallels and highlighting differences as the existing literature allows.

Reinstatement of Drug-Taking Behavior as a Method of Assessing Incentive Motivational Properties of Drugs

Noncontingent “priming” presentations of positive reinforcers (or incentive events) can enhance and reinstate previously acquired instrumental responding for these reinforcers. We describe how this phenomenon may be used to study the motivational control of drug-taking behavior and the relapse to drug-taking in drug-free individuals.