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

Stewart, Jane; Wit, Harriet de

doi:10.1007/978-1-4612-4812-5_12

Cited by 144 publications

(108 citation statements)

References 54 publications

(49 reference statements)

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“…Following varying periods of abstinence (39,40) and extinction, priming injections of cocaine or re-exposure to a cocaine-paired cue can reinstate drug-seeking behavior, as measured by responses on the manipulandum (e.g., nose-port) that previously resulted in cocaine delivery (41,42). This "reinstatement model" is commonly used in rodents to study relapse (for review, see refs.…”

Section: Resultsmentioning

confidence: 99%

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

Flagel

Chaudhury

Waselus

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with "temperament," including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/ bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor. addiction | dopamine | fibroblast growth factor | nucleus accumbens | reinstatement A pproximately 16% of adults in the United States report drug use within the past year (1). However, not everyone who experiments with drugs becomes an addict, as an estimated 8.5% of the population, or 25 million Americans, meet Diagnostic and Statistical Manual of Mental Disorders IV (2) criteria for substance abuse and dependence (1). Environmental and societal factors play a role in addiction liability (e.g., refs. 3-5), and there is ample evidence demonstrating a role for genetic factors (e.g., refs. 6-10). However, studying the interplay among these factors is difficult in human studies because of the inability to control for environmental factors and the challenge of parsing causes from consequences. Preclinical animal models are therefore essential for defining the complex interactions between genes and environment, and uncovering the neural mechanisms that might render an individual more susceptible to drug addiction. The first animal model characterizing individual differences in the propensity to take drugs of abuse was introduced over two decades ago by Piazza et al. (11), who showed that, like humans, only some rats readily self-administer such drugs. Furthermore...

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Section: Resultsmentioning

confidence: 99%

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

Flagel

Chaudhury

Waselus

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Cross-priming has often been investigated within a reinstatement paradigm; this refers to the resumption of a previously extinguished drugseeking response by noncontingent exposure to the priming drug (Shalev et al, 2002;Stewart and de Wit, 1987). The precise mechanisms that mediate cross-priming and reinstatement are complex (Schenk and Partridge, 1999;Shalev et al, 2002;Spealman et al, 1999).…”

Section: Lexical Salience Task and Amph-induced Semantic Activationmentioning

confidence: 99%

“…Drug priming specifically refers to the case in which the noncontingent delivery of a pharmacological agent activates or reinstates a previously established drug-seeking or drug-taking response (Stewart and de Wit, 1987). Like drug reinforcers, gambling has been found to produce priming-like effects in problem gamblers.…”

Section: Introductionmentioning

confidence: 99%

Amphetamine Primes Motivation to Gamble and Gambling-Related Semantic Networks in Problem Gamblers

Zack

Poulos

2003

Neuropsychopharmacol

132

101

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“…In the reinstatement model, laboratory animals are trained to self-administer drugs and are then given extinction training during which lever presses are not reinforced. Reinstatement of lever responding (the operational measure of drug seeking) is then determined after exposure to drug or non-drug stimuli (de Wit and Stewart, 1981;Stewart and de Wit, 1987;Shaham et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The Anxiogenic Drug Yohimbine Reinstates Palatable Food Seeking in a Rat Relapse Model: a Role of CRF1 Receptors

Ghitza

Gray

Epstein

et al. 2005

Neuropsychopharmacol

143

156

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The major problem in treating excessive eating is high rates of relapse to maladaptive eating habits during diet treatments; this relapse is often induced by stress or anxiety states. Preclinical studies have not explored this clinical problem. Here, we adapted a reinstatement model (commonly used to study relapse to abused drugs) to examine the role of stress and anxiety in relapse to palatable food seeking during dieting. Rats were placed on restricted diet (75-80% of daily standard food) and for 12 intermittent training days (9 h/day, every other day) lever-pressed for palatable food pellets (25% fat, 48% carbohydrate) under a fixed ratio 1 (20-s timeout) reinforcement schedule. Subsequently, the rats were given 10 daily extinction sessions during which lever presses were not reinforced, and were then injected with yohimbine (an a-2 adrenoceptor antagonist that induces stress and anxiety in humans and non-humans) or given a single food pellet to assess reinstatement of food seeking. The rats rapidly learned to lever press for the palatable pellets and across the training days the ratio of timeout nonreinforced lever presses to reinforced lever presses progressively increased more than three-fold, suggesting the development of compulsive eating behavior. After extinction, yohimbine injections and pellet priming reliably reinstated food seeking. The corticotropin-releasing factor 1 (CRF 1 ) receptor antagonist antalarmin attenuated the reinstatement induced by yohimbine, but not pellet priming. Antalarmin also reversed yohimbine's anxiogenic effects in the social interaction test. These data suggest that CRF is involved in stress-induced relapse to palatable food seeking, and that CRF 1 antagonists should be considered for the treatment of maladaptive eating habits.

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

Cited by 144 publications

References 54 publications

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

Amphetamine Primes Motivation to Gamble and Gambling-Related Semantic Networks in Problem Gamblers

The Anxiogenic Drug Yohimbine Reinstates Palatable Food Seeking in a Rat Relapse Model: a Role of CRF1 Receptors

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