Drug abstinence: exploring animal models and behavioral treatment strategies.

Psychopharmacology (2014) 231:2045–2058 DOI 10.1007/s00213-014-3517-2

REVIEW

Drug abstinence: exploring animal models and behavioral treatment strategies Joshua A. Peck & Robert Ranaldi

Received: 30 October 2013 / Accepted: 19 February 2014 / Published online: 16 March 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Background and rationale An enormous amount of resources has been devoted to the development of pharmacotherapies for drug addiction, with relatively little or no long-term success reported. The current review argues that a successful drug addiction treatment program will likely be one that focuses on both the neural mechanisms and the environmental contingencies that mediate drug use. Further, because the neural mechanisms and environmental factors that support abstinence in humans are similar in laboratory animals, several animal models of abstinence and relapse have been developed. Thus, this review also compares the similarities in the mechanisms that lead to abstinence between animals and humans. Objective We evaluate the construct and face validities of the behavioral strategies that help support human drug abstinence. Further, we crucially evaluate animal models by assessing their validity and utility in addressing human behavior that leads to long-term abstinence. Conclusions We found that the behavioral strategies with the greatest likelihood of supporting long-term abstinence are those that are carried out in drug addicts’ natural setting(s) and while drug is readily available. Further, the behavioral strategies that may be most successful in supporting abstinence in humans are those that employ both positive consequences for abstinent related behavior and negative consequences for continued drug seeking or taking. Moreover, the animal models of abstinence and relapse that more closely represent the factors that support long-term abstinence in J. A. Peck : R. Ranaldi Graduate Center, City University of New York, New York, NY 10016, USA R. Ranaldi (*) Psychology Department, Queens College, 65-30 Kissena Blvd, Flushing, New York, NY 11367, USA e-mail: [email protected]

humans are those that limit their use of extinction or forced abstinence and present negative consequences for drug seeking and taking. Keywords Addiction . Abstinence . Animal model . Construct validity . Face validity . Extinction . Reinstatement . Relapse . Review Drug addiction is a serious and growing epidemic in the USA and costs upwards of half a trillion dollars each year, when considering the combined medical, economic, criminal, and social impact (www.nida.nih.gov). Every year, illicit drug and alcohol abuse contribute to more than 100,000 deaths and tobacco to 440,000 deaths in the USA. This has led to an increasing need for effective drug treatments to help addicted individuals stop compulsive drug seeking and use. Although pharmacological treatments can safely manage acute physical symptoms of withdrawal and can, for some, pave the way for effective long-term addiction treatment, medication alone is rarely sufficient to help addicted individuals achieve long-term abstinence. Moreover, tremendous resources have been devoted to the development of pharmacotherapies for drug addiction, with relatively little or no longterm success (Kreek et al. 2002; Koob et al. 2009). Thus, a successful drug addiction treatment program would likely focus on both the neural mechanisms and the environmental contingencies that mediate drug use. Research shows that combining treatment medications with behavioral therapy is the best way to help sustain long-term abstinence (Silverman et al. 1996; Haug et al. 2004; Carroll and Onken 2005; Higgins et al. 2005). Further, behavioral treatment approaches for drug addiction provide incentives to remain abstinent, and teach important life skills that will help support abstinence in the presence of stressors or other environmental cues that may trigger intense craving for drugs. Increasing our understanding

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Psychopharmacology (2014) 231:2045–2058

about which behavioral factors determine successful longterm abstinence will lead to more efficient treatment strategies in drug addiction. This review will focus on the current behavioral treatments that help support abstinence. Also, the review will discuss the validity of current animal models that have been developed to investigate abstinence in drug addiction.

cessation of drug use. During abstinence, addicted individuals typically experience the unpleasant symptoms of withdrawal, which can be physiological (e.g., sweating, fever, nausea etc.) and/or psychological (e.g., craving). The final component of the drug addiction cycle is relapse. Relapse can be defined as the resumption of drug use after a period of abstinence.

Definition of terms

Behavioral strategies that support abstinence

Addiction is defined as a chronic, relapsing brain disease characterized by compulsive drug seeking and use, despite harmful consequences (www.drugabuse.gov). We put forth that drug addiction can be seen as a neuro-behavioral syndrome arising out of an interaction among several factors including the (genetic) predisposition of an individual, the positive reinforcement effects of the drug, the historical and current environmental situational factors and neural adaptations to accumulating drug use. Others have made the argument that for some, drug addiction results from a sequential three-step interaction between individual vulnerability, the amount of drug exposure, and loss of control of drug intake (resulting from loss of synaptic plasticity in brain reward areas)(Piazza and Deroche-Gamonet 2013). Further, drug addiction can be characterized as a cycle that consists of several features such as, acquisition, dependence, tolerance, withdrawal, abstinence, and relapse. Some of these features will be discussed throughout the review and will be defined here. Acquisition is the learning of the drug taking response. After the organism learns the drugtaking response, future responding is maintained over time. Dependence is defined as the compulsive use of illicit drugs, despite the harmful consequences of obtaining and/or using the substance (American Psychiatric Association 2013). There are two types of dependence: physiological and psychological. Physiological dependence refers to a decrease in responsiveness to a drug after repeated administration followed by negative physical symptoms due to discontinuation of the drug or dosage reduction. Psychological dependence is an increase in drug consumption as a result of psychological CRAVING. Table 1 provides a glossary of terms used in our review (UPPERCASE LETTERS in the text). For example, heroin addicts experience both physiological dependence (e.g., flu-like symptoms) and psychological dependence (e.g., craving), while cocaine addicts typically report experiencing only psychological dependence (Kalant 1977; Wise 1988). Tolerance is a decrease in susceptibility to the effects of a drug due to its continued administration that can be a result of physiological and/or psychological dependence. An important feature of the drug addiction cycle and the primary focus of the current review is abstinence. Abstinence can be defined as the self-imposed or forced

In this section, behavioral strategies that help support abstinence will be reviewed. Each strategy will be evaluated according to its efficacy in supporting human long-term abstinence and its advantages and limitations in terms of achieving drug abstinence. It should be noted that generally none of the abstinence strategies discussed here has led to long-term abstinence (1 year or more) for human drug addicts. Further, it is important to convey that a large number of addicted individuals that remain abstinent for long periods of time have done so without the help of overt interventions. Lastly, comparisons among treatment strategies on their efficacies to support abstinence should be made with caution as the drug used, drug-using population, the absence of proper control conditions, and definitions of relapse differ across the studies discussed below. The behavioral strategies that will be discussed include: counterconditioning, drug-paired cue exposure, contingency management, and environmental enrichment (see Table 2). Counterconditioning In counterconditioning, a stimulus that was originally associated with one event (e.g., shock) is later associated with a different event (e.g., food) (Copemann and Shaw 1976; Lovibond and Dickinson 1982). For example, a heroin syringe (CONDITIONED STIMULUS, CS) being paired with an electric shock, instead of the drug (UNCONDITIONED STIMULUS, US). Counterconditioning has been shown to be effective in prolonging abstinence when aversive events are reliably paired with the drug or drug-paired cues that could elicit relapse (Frawley and Smith 1990; Bordnick et al. 2004). Bordnick et al. (2004) found that when aversion therapy was used in which a powder that resembles cocaine (conditioned drug cue) is paired with injections of emetic drugs or mild electric shock applied to the wrist, human addicts reported significantly less craving for the drug, thereby supporting abstinence. Further, when the addicts were exposed to drug-paired cues, they reported experiencing a negative hedonic reaction compared to the positive hedonic reaction they felt with past drug use. Interestingly, counterconditioning procedures have led to some common pharmacological treatments for


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Table 1 Glossary of terminology Conditioned reinforcer

Conditioned stimulus Construct validity

Context

Psychological craving Discriminative stimulus

Extinction

Face validity Drug “lapse” Reinstatement

Renewal

Resurgence

Unconditioned stimulus

A stimulus that acquires reinforcing properties through repeated pairing with the primary reinforcing effects of an unconditioned stimulus (e.g., drug) (Skinner 1938). A unimodal or bimodal stimulus that acquires conditioned properties through repeated pairing with an unconditioned stimulus (Pavlov 1927). A term that refers to a similarity in the mechanisms underlying behavior between the animal model and the natural (human) phenomenon under study. Static multimodal background stimuli which constitute a setting where CS− unconditioned stimulus and/or response-unconditioned stimulus associations can form. Contextual stimuli are presented throughout an experimental session, independent of the subject’s behavior (Bouton and Bolles 1979). A self-report of the desire to seek or take a drug(s). A unimodal or bimodal stimulus that signals the particular reinforcement contingency in the course of discrimination training. It is presented independent of the subject’s behavior. In drug addiction, the SD signals drug availability, whereas SΔ signals drug unavailability (Skinner 1938; Stolerman 1992). Experimental contingency during which instrumental responses have no programmed consequences (e.g., no drug delivery) (Pavlov 1927; Skinner 1938). The extent of overt similarity between the model and the natural (human) phenomenon under study. The single occurrence of drug taking following a period of drug abstinence in humans (Wikler 1973). Recovery of a previously extinguished instrumental or Pavlovian conditioned response upon exposure to un-extinguished CS or context, small amount of drug, or stress (Pavlov 1927; Bouton and Swartzentruber 1991; Grimm et al. 2001; Shaham and Miczek 2003). Recovery of a previously extinguished instrumental or Pavlovian conditioned response upon re-exposure to the CS in the training context after the CS is extinguished in an alternate context (Bouton and Bolles 1979; Bouton and Swartzentruber 1991). When a previously acquired behavior is no longer reinforced while a second, novel behavior is reinforced and subsequent extinction of that new behavior results in the recovery “resurge” of the original reinforced behavior (Leitenberg et al. 1970). A unimodal or bimodal stimulus that innately elicits a reflexive response (without conditioning) (Pavlov 1927).

drug addiction, such as disulfiram (tradename: Antabuse), an aversive substance when mixed with drinking alcohol. Counterconditioning procedures help support human drug abstinence by strengthening the alternate abstinence behaviors through reinforcement, and punishing drug-taking behaviors by pairing drug and drug-paired cues with aversive consequences (Van Gucht et al. 2010; Kerkhof et al. 2011). In fact, some studies have demonstrated that using counterconditioning to decrease the reinforcing value of cues paired with nondrug reinforcers in both animal and human models is more effective than when using EXTINCTION procedures alone (Lovibond and Dickinson 1982; Kerkhof et al. 2011). However, the context in which the counterconditioning procedure is conducted is important. In a study conducted by Peck and Bouton (1990), rats received CS-shock pairings in one context

(A) and CS-food pairings in another (B) and they found that the original fear performance replaces responding for a food stimulus when the animals are placed back in the original context (A). As such, counterconditioning produces learned behavior that comes under the stimulus control of the situation in which such procedures are presented (Bouton 2004). Therefore, in order for counterconditioning to be successful in longterm abstinence, this behavioral strategy may need to be executed across the different contexts in which drug use occurs. In summary, counterconditioning works to support abstinence through the use of aversive consequences; the stimulus–response relationship is modified by pairing a stimulus (either drug or drug-paired cues) with an aversive event, apparently diminishing the reinforcing efficacy of the drug or drug cues.

Contingency Management Drug-paired cue exposure Counterconditioning

Table 2 Behavioral Strategies that support human drug abstinence

Applications The stimulus–response Exposure to a stimulus (CS) that has been reliably Based on principles of operant conditioning where Typically, presenting a choice between drug and relationship is modified by paired with drug (US) in the absence of the (US) a drug or drug cue functions as an SΔ (signals other types of rewards (e.g., social interaction pairing a stimulus (either in order to reduce the physiological effects and drug unavailability) for drug-seeking behavior, and exercise) and where the organism chooses drug or drug-paired cues) psychological craving to that (CS), or drug cue and alternative abstinence behavior serves as a the alternative reward(s) over drug with an aversive event discriminative stimulus SD for the availability (shock or emetic drug) of rewards other than the drug Strengths Supports abstinence by Effective procedure to decrease craving and The use of both positive and negative A few studies have shown that when stimulation or strengthening the alternative withdrawal when exposed to drug-paired cues consequences to control drug seeking by reward is derived from a source other than the abstinence behaviors while in abstinence Further, the addict is taught rearranging the drug user’s environment so that drug itself (enrichment), drug users have through reinforcement abstinence strategies (e.g., deep relaxation drug abstinence is positively reinforced and remained abstinent longer than those who did while, drug-taking behaviors training) in the presence of drug-paired cues that drug use results in an immediate loss of not receive such alternative stimulation or are punished by pairing drug reportedly decrease drug craving and reinforcement rewards and drug paired cues withdrawal with aversive consequences Limitations Counterconditioning as a High individual relapse rates when returning back Only promotes abstinence when the contingency is Most studies investigating the effects of strategy to support to their natural setting and are exposed to drugin place; once the contingency is removed, the environmental enrichment as a strategy to abstinence may be context paired CSs (renewal of drug seeking) probability of remaining abstinent decreases support abstinence have been conducted with specific animals


Environmental enrichment

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Drug-paired cue exposure Cue exposure under extinction conditions is another treatment strategy that has been used to support drug abstinence in humans. In cue exposure, the person is exposed to a stimulus (CS) that has been reliably paired with drug (US) in the absence of the US (extinction procedure) in order to reduce the physiological effects and psychological craving to that CS. Cue exposure therapy has been demonstrated in some studies to decrease craving and withdrawal when exposed to drugpaired cues while in abstinence (McLellan et al. 1986; Childress et al. 1988; O’Brien et al. 1988). Further, an important component of drug cue exposure treatment is that addicts are taught abstinence strategies (e.g., deep relaxation training) in the presence of drug-paired cues that reportedly decrease drug craving and withdrawal. Childress et al. (1988) examined cue exposure with opiate users who were exposed to stimuli paired with opiate use or to neutral stimuli. Opiate-related stimuli consisted of a 10-min video simulating drug buying, selling, and heroin selfadministration. After the cues were presented, the participants could conduct a mock “cook-up” ritual using a powder that resembled heroin, and were told that it was not real. For the neutral stimulus video, participants were exposed to a video of equal length, in which they watched a person playing a video game. The physiological measures that were taken included peripheral skin temperature, galvanic skin resistance, and heart rate. An additional subjective measure was taken in the form of the patient rating on a scale of 1 to 10 how much they craved an opiate, felt an opiate high, or experienced withdrawal symptoms under each set of stimulus conditions. Childress et al. (1988) found that during drug cue exposure methadone patients showed greater decreases in skin temperature and galvanic skin response, which are typical symptoms displayed when individuals abstain from using drugs. Further, methadone outpatients showed increases in craving and exhibited flu-like withdrawal symptoms when observing the video with opiate paired cues. These findings suggest how critical drugpaired cues in natural settings are and the increased possibility for an individual to relapse when exposed to these cues while abstaining from the drug. Cue exposure therapy alone has not proved to be successful in promoting long-term abstinence in drug addicts. For example, Childress et al. (1993) found that many of the patients that were in outpatient methadone cue exposure treatment continued to report subjective feelings of craving and withdrawal while in abstinence for at least 30 days. Further, a common outcome of this strategy is that individuals relapse when they return to their natural setting, and the cues that were previously extinguished in the experimental setting now become reconditioned (Rose and Levin 1991). Therefore, when using a drug cue exposure extinction procedure, it may be critical that the techniques be applied in the natural environment, where


addicts typically experience the drug-paired CSs, to help prevent the renewal of drug seeking in the drug-conditioned contexts (Rose and Levin 1991; Conklin and Tiffany 2002).

Contingency management The most thoroughly investigated behavioral strategy that supports drug abstinence is contingency management. This strategy is based on principles of operant conditioning in which behavior that is followed by a reinforcer is likely to be repeated. The basic strategy is to rearrange the drug user’s environment so that drug abstinence is positively reinforced and drug use results in an immediate loss of reinforcement. That is, a drug or drug cue should function as an SΔ (signals drug unavailability) for drug-seeking behavior, and alternative abstinence behavior should serve as a discriminative stimulus SD for the availability of rewards other than the drug. Procedurally, abstinence behavior is reinforced by the delivery of positive reinforcers (such as vouchers to buy goods). However, if the addict is exposed to drug cues and chooses to consume drug, the voucher is not delivered (drug seeking is not reinforced). Therefore, contingency management programs use both positive and negative consequences to control drug seeking (Hall et al. 1990). Research has found that the use of contingent vouchers leads to increased durations of abstinence (Higgins et al. 1994; Schottenfeld et al. 2005) and the number of clients who fulfill specified periods of abstinence (Higgins et al. 1994; Katz et al. 2004). For example, Higgins et al. (1994) found the use of contingent vouchers increased abstinence from 6.0 to 11.7 weeks while Katz et al. (2004) showed an increase from 18 to 31 % in the number of patients remaining abstinent during a weekend when contingency vouchers were delivered. However, the use of contingency management as a strategy to support long-term abstinence has its limitations. For example, research has shown that abstinence only increases during periods of escalating value of vouchers (Schottenfeld et al. 2005). Moreover, this strategy only promotes abstinence while the contingency is in place (Hall et al. 1990). For example, Carroll and Onken (2005) found that participants who had remained abstinent due to the delivery of voucher rewards relapsed once the voucher intervention was removed. For an individual to continue abstinence-related behaviors without the delivery of vouchers, one must transfer the function previously served by voucher rewards to behaviors that are in-and-of-themselves reinforcing and that occur in a broad range of contexts. However, much of the contingency management literature to date has not reinforced abstinence across a broad range of non drug-seeking behaviors or contexts. Consequently, the effectiveness of contingency management as a strategy to support long-term abstinence has not been empirically supported.

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Environmental enrichment The above-referenced contingency management studies employed the delivery of response-contingent alternative rewards to help support drug abstinence. However, in the few studies conducted with humans, the use of non-contingent procedures that deliver alternative rewards, such as environmental enrichment, have also been shown to be effective in supporting abstinence (Solinas et al. 2010). For example, human drug addicts that participate in non-drug pleasurable activities remain abstinent longer than those who do not engage in such activities (Schottenfeld et al. 2000; Setlow 2008; Schnabel 2009), suggesting that environmental enrichment could support human drug abstinence. Further, in humans, researchers have suggested a link between the removal of alternative, reinforcing events and increases in drug intake or instances of relapse after periods of abstinence. For example, Falba et al. (2005) examined data from a Health and Retirement study in order to explore the relationship between involuntary job loss and smoking intensity as well as relapse in abstinent smokers. Falba et al. (2005) found that involuntary job loss contributed significantly to elevated levels of smoking in individuals who already smoked. Furthermore, risk of relapse doubled after job loss in ex-smokers. Environmental enrichment (EE) can be defined as the noncontingent delivery of alternative non-drug rewards such as, food, social interaction, novelty objects, and voluntary physical activity either in the presence of drug (concurrent) or in its absence (non-concurrent) (Carroll 1993; Zlebnik et al. 2010; Chauvet et al. 2009; Thiel et al. 2009). Access to nondrug alternatives can impede or prevent acquisition and decrease drug-maintained responding (Carroll et al. 1989; Lynch et al. 2010 2013). For example, animal studies have shown that exercise reduces cocaine’s reinforcing effects when concurrently available with the drug (Smith et al. 2008; Zlebnik et al. 2012) as well as facilitates extinction and attenuates relapse (Cosgrove et al. 2002; Grimm et al. 2008; Zlebnik et al. 2010). Further, the removal of such non-drug alternatives may also result in increased drug taking (Carroll and Boe 1982; Podlesnik et al. 2006). Typically, environmental enrichment as an abstinence enhancing treatment strategy in animals is demonstrated by presenting a choice concurrently between the drug and other types of rewards (e.g., food, social interaction, and exercise) and where the organism chooses the alternative reward(s) over drug. Moreover, environmental enrichment is typically used during periods of abstinence so that the organism can learn that other choices besides relapse are concurrently available. For example, under certain conditions, several studies have demonstrated that if animals have the choice between drug and other types of rewards (e.g., food, social interaction, and exercise) they will typically prefer the alternative rewards over

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drug (Carroll et al. 1989; Carroll 1993; Rodefer and Carroll 1996; Panksepp et al. 1997; Lett et al. 2000; Cosgrove et al. 2002; Mattson et al. 2001; Bevins and Besheer 2005). Research has also demonstrated that environmental enrichment provided non-concurrently with the drug attenuates the probability of drug seeking (Lenoir and Ahmed 2007; Ahmed 2005). Chauvet et al. (2009) and Thiel et al. (2009) found that environmental enrichment reduced responding in extinction and in reinstatement tests where reinstatement was induced by the presentation of a discrete cocaine cue. Ranaldi et al. (2011) examined the effects of environmental enrichment on extinction responding and on cocaine context renewal of responding in rats. They found that environmental enrichment attenuated responding in extinction and in a drug-context renewal test compared to non-enriched subjects. Ranaldi et al. (2011) speculated that the introduction of rewarding stimulation that is experienced in the enriched environment might reduce the significance (or effectiveness) of drug-related stimuli through a contrast mechanism. Grimm et al. (2013) found that brief exposure to novel or enriched environments non-concurrently with sucrose, reduced sucrose cue-reactivity and consumption in self-administrating rats after 1 or 30 days of forced abstinence compared to control rats. The authors noted that exposure to enrichment or novelty may have created a contrast such that environmentally enriched rats responded significantly less for the sucrose-paired cue because it was no longer as reinforcing as the enriched or novel context from where they were just removed (Reynolds 1961; Grimm et al. 2013). If this is so, then environmental enrichment could potentially be an effective treatment for cocaine, or other types of addiction. The common feature of the studies reviewed in this section is that they demonstrate when stimulation or reward is derived from a source other than the drug itself (enrichment), there is a reduction in the reinforcing effects of, or motivation for, the drug, thereby sustaining abstinence. However, these results have largely only been found in animal studies using environmental enrichment. In humans, whether or not environmental enrichment can sustain long-term abstinence is relatively unknown (Solinas et al. 2010). Further, given that there is promising evidence that environmental enrichment may indeed support drug abstinence in animals, it is imperative that this possibility be explored in humans. An optimal behavioral strategy that supports long-term abstinence When evaluating the behavioral treatment strategies just discussed, we should take note of the individual strengths each behavioral strategy provides in supporting abstinence. For example, the behavioral treatment strategies that employ not only positive consequences for remaining abstinent, but also aversive consequences for drug seeking (e.g., counterconditioning and contingency management) have been


somewhat successful in supporting short-term abstinence in humans. Further, a strength of the environmental enrichment approach is that it provides non-concurrent rewarding stimulation that seems to reduce the effectiveness of drug-related stimuli upon re-exposure to them, thereby supporting drug abstinence. However, research suggests that in general no singular abstinence strategy has led to long-term abstinence for human addicts. Perhaps, when taken collectively, the important features of each behavioral strategy discussed here could lead to an optimal behavioral approach that sustains long-term abstinence.

Animal models of abstinence and relapse in drug addiction A serious problem for treatment of drug addiction is relapse to drug use after prolonged periods of abstinence (O’Brien 2005). In human drug addicts, craving and relapse during abstinence are often triggered by acute re-exposure to the drug, non-contingent drug-associated cues or stress (De Wit and Stewart 1983; O’Brien 2005; Sinha et al. 2011). Successful treatment of drug addiction must involve increasing our understanding of both the neurobiological and environmental factors that support long-term abstinence. Further, because the factors that support abstinence in humans and laboratory animals are similar, several animal models of abstinence have been developed. Here, we review animal models of abstinence and relapse and evaluate their validity and utility in addressing human behavior that leads to long-term abstinence. Moreover, it should be emphasized that the primary focus of this review is to evaluate the factors that lead to abstinence. As such, the current review has deliberately focused solely on how each animal model procedurally induces abstinence in order to investigate relapse. When evaluating the FACE VALIDITY of different animal models of abstinence, the authors will compare the overt similarities between the animal models discussed and the natural phenomenon of human drug abstinence. For example, an animal model that employs contingent (self-initiated) drug exposure (as is the case in humans) instead of non-contingent (passive) drug exposure would have stronger face validity. Further, for CONSTRUCT VALIDITY, the current review will be comparing the similarity in the mechanisms underlying abstinence behavior between animal models of abstinence and human drug abstinence. For example, an animal model that uses instrumental extinction training (withholding of the drug) instead of inducing abstinence in the presence of the drug (as it is in humans) that may better capture the neural and environmental mechanisms of abstinence in humans would have less construct validity. To evaluate the face and construct validities of animal abstinence models several procedural factors must be


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considered. First, whether drug exposure is non-contingent or contingent crucially influences abstinence behavior (Carroll and Comer 1996; Epstein et al. 2006). Second, human drug abstinence is rarely a result of explicit extinction therapy in clinical settings or in the drug user’s natural environment. Thus, animal models that assess abstinence in the presence of the drug, instead of during instrumental extinction training are preferable when considering drug abstinence in humans. Lastly, in humans, abstinence involves the conflict situation of choosing between drug taking or seeking that are accompanied by aversive consequences and cessation of drug use (Epstein and Preston 2003; Epstein et al. 2006; Cooper et al. 2007). That is, human abstinence often occurs because drug taking becomes associated with aversive consequences that outweigh the drug’s rewarding effects. Therefore, an abstinence model that captures these features of abstinence—the negative consequences occurring during drug seeking or after drug taking—would more closely approximate the human drug abstinence condition. The animal models of abstinence

and relapse that will be discussed include: renewal, reinstatement, drug-predictive discriminative stimulus-induced reinstatement, resurgence, abstinence model, punishment-based abstinence, and conflict-based abstinence (see Table 3). Renewal model Renewal refers to response recovery produced by a change in context after extinction (Bouton and Bolles 1979; Bouton and Swartzentruber 1991). A common form is ABA renewal in which the subject returns to the original conditioning context after extinction. That is, initial training takes place in one context (A), extinction in a second context (B), and then responding is renewed once the subject is returned to the original training context (A). This type of renewal is observed in both classical and operant conditioning (Bouton and Swartzentruber 1991). Typically, self-administration studies using the renewal model are carried out by training animals to perform an

Table 3 Procedural comparisons of abstinence models of addiction Animal model

Training

Abstinence

Procedural limitations

Renewal (Bouton and Bolles 1979; Bouton and Swartzentruber 1991)

Self-administration

Extinction of operant behavior

Reinstatement (Pavlov 1927; Bouton and Swartzentruber 1991; Grimm et al. 2001; Shaham and Miczek 2003) S+-induced reinstatement (Koob 2000; Ciccocioppo et al. 2002)

Self-administration

Extinction of operant behavior

Self-administration

Extinction of operant or forced removal from drug context

Resurgence (Leitenberg et al. 1970, 1975; Podlesnik et al. 2006; Winterbauer and Bouton 2010)

Self-administration

Abstinence (Neisewander et al. 2000; Grimm et al. 2001; Grimm 2002; Pickens et al. 2011)

Self-administration

Extinction of the drug-reinforced response, while operant responding on other manipulandum leads to the delivery of a non-drug reward Forced removal from drug context

Punishment-based abstinence (Smith and Davis 1974; Panlilio et al. 2003; Panlilio et al. 2005)

Self-administration

Lever presses for drug are suppressed by response-contingent shock

Conflict-based abstinence (Cooper et al. 2007; Barnea-Ygael et al. 2012; Peck et al. 2013)

Self-administration

Introduction of an electrified grid floor that must be crossed to continue drug use, while increased shock intensity leads to the termination of the drug-reinforced response

Abstinence induced by operant extinction in a different context than where drug is used. Model does not capture negative consequences of human drug use Abstinence induced by extinction does not model abstinence in humans. Model does not capture negative consequences of human drug use Abstinence induced by either extinction or forced removal does not model abstinence in humans. Model does not capture negative consequences of human drug use Abstinence induced by extinction does not model abstinence in humans. Model does not capture negative consequences of human drug use Abstinence induced by forced removal versus self-imposed does not model abstinence in humans. Model does not capture negative consequences of human drug use Does not fully model human abstinence because the aversive consequences usually occur AFTER taking the drug. Model does not capture the aversive consequences related to drug -seeking Model does not capture the aversive consequences related to drug taking

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instrumental response with drug reinforcement in a distinct environmental context (A) where drug delivery is paired with CS presentations (Bouton 2002; Crombag and Shaham 2002; Kearns and Weiss 2007). After self-administration training, subjects’ responding is extinguished in a different context (B) but in the presence of the previously drug paired CS. On the test day, subjects are given response-contingent access to the CS in the previously drug-paired context (A), which results in the RENEWAL of responding, according to an ABA design. The possibility for ABA and AAB renewal was assessed in rats trained to self-administer a heroin–cocaine mixture (i.e., speedball) in the presence of discrete drug cues (Crombag and Shaham 2002). Following extinction to the drug cues (drug was removed) in the same (A) or different (B) context, the rats were tested for renewal (drug cues were present, but no drug available) in either context. They found a strong ABA renewal effect, but did not demonstrate AAB renewal. Surprisingly, exposure to a novel context fails to renew drug seeking after extinction training in the drug paired context (AAB), where other studies using either the AAB or ABC procedure with shock have found the renewal effect (Bouton and Bolles 1979; Bouton and Ricker 1994; Crombag and Shaham 2002; Fuchs et al. 2008). However, it is important to note that in animal studies the amount of acquisition training, contextual similarity, and acquisition in multiple contexts strongly influences both the strength and type of renewal (e.g., AAB or ABC renewal) after the extinction of instrumental learning (Bouton et al. 2011; Todd et al. 2012). For example, Todd et al. (2012) found that ABA and ABC forms of renewal were both strengthened by increasing the amount of acquisition training in operant responding for food either in the same context or in multiple contexts. Nevertheless, research with animals has reliably demonstrated ABA renewal with a variety of drugs including cocaine, heroin, nicotine, and alcohol (Bossert et al. 2004; Fuchs et al. 2008; Diergaarde et al. 2008; Chaudhri et al. 2008). As discussed previously, when using drug cue exposure as a behavioral strategy for abstinence in humans, drug addicts who acquire a drug habit in one environment, e.g., home, and undergo cue-exposure therapy in a clinic are likely to experience a renewal of drug craving (leading to relapse) when confronted with drug-associated stimuli upon returning home. A major strength of the renewal model is that it captures this feature of context dependent drug relapse. Moreover, both human and animal drug abstinence research have found that when the environment for extinction and post-extinction testing are the same, renewal is less likely to occur (Collins and Brandon 2002; Crombag and Shaham 2002; Thewissen et al. 2006). Thus, when using a drug cue exposure extinction procedure to support abstinence, it may be important that these techniques be applied in the same environments where previous drug use happened, to help protect against the renewal of drug-seeking


behavior in the many drug-conditioned contexts (Rose and Levin 1991; Conklin and Tiffany 2002). Lastly, the renewal model has led to the understanding of how behavioral strategies that use alternative rewards work to support abstinence within the drug context. There is evidence that suggests that alternative forms of reinforcement for recovering drug addicts may help to strengthen abstinence by diminishing the probability of drug renewal (Kearns and Weiss 2007; Ranaldi et al. 2011). For example, when pairing drug-related stimuli with alternative forms of reinforcement (e.g., food), the extent to which contextual renewal occurred was significantly reduced (by 90 %) in cocaine-seeking rats (Kearns and Weiss 2007). This evidence along with the research of others who have used a similar renewal model (Ranaldi et al. 2011) suggests that alternative forms of reinforcement as a strategy to support abstinence in recovering addicts may help to minimize the extent to which renewal occurs in the drug-associated context. A major limitation when evaluating abstinence using the renewal model (as well as other abstinence models we will discuss) is that animals cease to self-administer drug for one reason: it is no longer available (extinction). Further, there are no aversive consequences associated with drug use. In contrast, drug abstinence among human drug abusers typically results from choice, while the drug remains available (Epstein et al. 2006; Cooper et al. 2007; Peck et al. 2013). Further, in humans, abstinence involves the conflict of choosing between continued drug taking or seeking that are accompanied by aversive consequences and cessation of drug use (Epstein and Preston 2003; Epstein et al. 2006; Cooper et al. 2007). Therefore, explicit extinction training before renewal testing reduces both the face and construct validities of the model because the drug is made unavailable and there are no aversive consequences for continued drug seeking. Reinstatement model The reinstatement model is currently the most commonly used animal model to study the repeating cycle of abstinence and relapse (Carroll and Comer 1996; Shaham and Miczek 2003). In this model, laboratory animals are trained to self-administer drug accompanied by a discrete stimulus (e.g., tone, light), usually by pressing a lever. Then, after extinction of the drugtaking response by withholding the drug reinforcer, nonreinforced REINSTATEMENT of responding is induced by either acute exposure to the discrete cue, drug priming, or stress (De Wit and Stewart 1983; Shaham and Stewart 1995; Meil and See 1996; Crombag et al. 2008; Feltenstein and See 2008). For example, studies with rats have shown that after extinction, cocaine or heroin seeking are reliably reinstated by acute injections of the drug or cues (discrete or discriminative) that are associated with the drug (Crombag et al. 2008; Feltenstein and See 2008). These results are consistent with


the data from abstinent drug-dependent patients who report experiencing stronger drug cravings that led to relapse shortly after acute exposure to a drug than before (Rose and Levin 1991). Therefore, the face validity of the reinstatement model is strong when considering the clinical scenario of human relapse that is elicited by acute re-exposure to the drug, drug-associated cues, or stress during abstinence (De Wit and Stewart 1983; O’Brien 2005; Sinha et al. 2011). However, in this model (as in the renewal model), abstinence is not achieved by choosing not to take drug while the drug is available; the previously self-administered drug is withheld and reduced drug-seeking results from extinction. The reinstatement model’s use of extinction coupled with the absence of negative consequences for drug seeking or taking reduces both the face and construct validities when comparing it to the human drug abstinence condition. Drug-predictive discriminative stimulus reinstatement model In this model, drug is delivered contingently upon instrumental responding in the presence of a passively presented DISCRIMINATIVE STIMULUS (SD). Further, the SD is paired with the response-contingent presentation of a conditioned stimulus (CS+) that is contiguously paired with drug presentations (US) (Koob 2000; Ciccocioppo et al. 2002). During nonreinforced sessions, drug reinforcement is withheld in the presence of a different discriminative stimulus (SΔ) and a time-out stimulus (CS−). Therefore, discriminative stimuli signal the availability or nonavailability of a reinforcer, and thereby provide motivation to engage in behavior that brings the organism into contact with the reinforcer (Koob 2000; Weiss et al. 2000). Moreover, the response-contingent CS, acting as a CONDITIONED REINFORCER, may contribute to the maintenance of subsequent drug seeking once initiated. After the acquisition of stimulus discrimination is demonstrated, subjects receive additional extinction training only in the presence of the discriminative stimulus SD and CS+, or undergo a drug-free abstinence period (forced removal from the context). On the reinstatement test sessions, drug seeking is assessed in the presence of the SD/CS+ and the SΔ /CS− using a repeated testing design (Ciccocioppo et al. 2002; Bachteler et al. 2005). The typical finding is that, during the test session, drug seeking is reinstated in the presence of SD/CS+. For example, Weiss et al. (2000) investigated the effect of drug-associated stimuli on cocaine self-administration in rats. An SD signaled response-contingent availability of intravenous cocaine while an SΔ signaled saline availability. Then, rats were subjected to repeated extinction sessions during which cocaine, in the presence of the SD, was withheld until the rats reached an extinction criterion. Subsequent reexposure to the cocaine SD produced resumption of drug

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responding in the absence of drug availability when compared to the SΔ. A major strength of this model is the demonstration that subjects can discriminate when drug is available; a condition often associated with drug relapse in humans is their ability to determine when the drug is available. Further, the model’s use of discriminative stimuli with animals has helped inform the effective abstinence strategy of contingency management in humans, where a drug or drug-paired cue comes to function as an SΔ for drug seeking, and cues that serve as an SD come to occasion abstinence-related behavior. Therefore, both face validity and construct validity are well represented in this model by the procedural use of discriminative stimuli and how they may serve a role in abstinence and the resumption of drug-seeking behavior in abstinent individuals (Schottenfeld et al. 2005). However, as in other animal models of abstinence, the use of extinction training or forced removal from the drug context (abstinence) and the absence of negative consequences for drug seeking or taking greatly decrease the discriminative model’s face and construct validities when comparing it to the human abstinence condition.

Resurgence model In this abstinence model, RESURGENCE refers to an operant behavior (e.g., pressing one lever for drug) that is no longer reinforced while a second, alternative behavior (e.g., pressing a different lever for food) is trained and reinforced. When that alternative behavior is extinguished, the first operant behavior can return or “resurge” (Leitenberg et al. 1970, 1975; Winterbauer and Bouton 2010). A typical resurgence experiment using drug includes rats that are trained to press on lever 1 for drug, and then lever presses on lever 1 are not reinforced (extinction), while responding on lever 2 is reinforced by the delivery of food. During test sessions, lever pressing is no longer reinforced on either lever or the observed resumption of drug responding on lever 1 (relapse) is characterized as “resurgence” (Podlesnik et al. 2006; Quick et al. 2011). Seemingly, the resurgence model has good face and construct validities when representing humans trying to reduce drug seeking while learning a new replacement behavior (e.g., exercise or painting) and undergo a “LAPSE” or relapse when the new behavior undergoes extinction. For example, contingency management abstinence strategies for drug taking are effective by reinforcing new healthy behaviors (e.g., delivery of money or vouchers contingent upon clean urine samples) to replace target ones. However, after the completion of contingency management treatment, the alternative reward is no longer delivered and a “resurgence” or relapse could be the result (Higgins et al. 2004; Long and Volpp 2008). As a representation of drug abstinence in humans,

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the use of extinction before resurgence testing reduces the model’s face and construct validities. Abstinence model Subjects in the abstinence model are first trained to perform an instrumental response with drug reinforcement either in the presence or absence of a CS (drug cue). After training, subjects remain in their home cages or an alternate context, which contains no instrumental manipulandum. The experimenterimposed drug-free period (forced abstinence) can range from days to months (Grimm 2002; Pickens et al. 2011). On the test day, subjects are re-exposed to the drug-paired context in the presence of the previously paired CS, which results in robust drug seeking. Moreover, the robust drug responding during the test session may be due to what has been referred to as “incubation of drug craving”; the time-dependent increase in cue-induced drug seeking after withdrawal from a drug (Lu et al. 2004; Pickens et al. 2011; Neisewander et al. 2000; Grimm et al. 2001; Marchant et al. 2013). In the abstinence model, the fact that subjects do not undergo explicit extinction training before testing provides some face validity to this model. Further, the abstinence model represents situations where human addicts are removed from the drug context thereby leading to forced abstinence. For example, when drug addicts are admitted into drug treatment centers or incarcerated and therefore are unable to obtain the drug(s). However, the procedural use of forced removal from the drug context to induce abstinence diminishes the model’s construct validity when considering the scenario of human drug abstinence that is not forced. That is, in humans, abstinence is often not forced, and results from the aversive consequences that coincide with drug seeking (Epstein and Preston 2003; Epstein et al. 2006; Cooper et al. 2007).

Toward an optimal animal model of drug abstinence The animal models of abstinence and relapse previously discussed (e.g., reinstatement model) attempt to measure abstinence by using environmental extinction, which does not allow for the organism to make a choice (take drug vs. not take drug). A more representative abstinence paradigm would allow the organism to take the drug after some behavioral response (as it often is in humans). Further, abstinence in humans occurs because the drug’s rewarding effects are outweighed by the aversive consequences of drug seeking or drug taking (Panlilio et al. 2003; Panlilio et al. 2005; Cooper et al. 2007; Barnea-Ygael et al. 2012). However, in most animal models, abstinence is achieved through extinction, not by the aversive consequences of drug seeking or taking. These important differences lead to a decrease in both the face


and construct validities of these animal models of abstinence compared to human drug abstinence. Thus, we argue that an animal model of abstinence should involve the following characteristics. The animals learn to self-administer the drug and then, while maintaining drug availability, aversive consequences (such as shock) should be introduced for drug seeking or delayed aversive consequences (again, such as shock) be introduced for drug taking. In both situations—aversive consequences for seeking or taking—the consequences should lead to abstinence. The use of aversive consequences for drug seeking or taking would be useful in further characterizing human drug abstinence. There have been a few animal models of drug abstinence developed to successfully incorporate aversive consequences during abstinence periods, while the drug remains available. In the following section, we will evaluate the two types of animal models that use either punishment or shockconflict to study drug abstinence. Punishment model Punishment-based relapse models have been developed in which drug-reinforced lever pressing is suppressed by lever press-contingent shock immediately after drug infusions (Panlilio et al. 2003, 2005). For example, Panlilio et al. (2003) trained animals to self-administer an opiate agonist and then instituted a lever press-contingent delivery of a shock accompanying the drug infusions. They found that this procedure suppressed the drug-reinforced operant response. Economidou et al. (2009), using a punishment procedure similar to that used by Panlilio et al. (2003), also found that when electric shock was contingent on the same drugreinforced lever press response that it suppressed cocainereinforced responding (i.e., lead to abstinence). The punishment model corresponds to the typical human abstinence drug situation, where the negative consequences of drug taking outweigh its hedonic (i.e., rewarding) effects (Panlilio et al. 2005). Because in this model, abstinence is not a result of extinction or forced removal from the drug context, it has improved face and construct validities when compared to other animal models discussed that use either extinction or abstinence by forced drug removal. Further, researchers have found that when extended access (compared to moderate access) is given to cocaine self-administering rats and subsequent electric shocks are delivered contingent upon the drug taking response, there is significantly less suppression of the drug-taking response (Deroche-Gamonet et al. 2004; Vanderschuren and Everitt 2004; Pelloux et al. 2007; Belin et al. 2009). Interestingly, these studies show that with extended cocaine self-administration in rats about 20 % were considered to be “resistant to punishment”. Therefore, the researchers have proposed that continuation of drug selfadministration in the presence of response-contingent shock


punishment can serve as an experimental procedure to study compulsive drug use (Deroche-Gamonet et al. 2004; Vanderschuren and Everitt 2004; Pelloux et al. 2007; Belin et al. 2009). Further, the ability to study compulsive use in animals provides the punishment model with strong construct validity because it approximates some of the defining features of human drug addiction. That is, in humans, addiction is not just the taking of drugs but the compulsive drug use maintained despite adverse consequences for the user (DSM-5). Therefore, the punishment model may provide insight into how to identify subjects at risk for subsequent development of severe cocaine addiction (compulsive use). However, this model does not fully represent the human drug condition because aversive consequences (e.g., loss of employment) occur usually a period of time AFTER taking the drug (Smith and Davis 1974; Panlilio et al. 2003; Panlilio et al. 2005). Therefore, the punishment model loses some construct validity when considering that humans rarely experience the major negative consequences (e.g., loss of employment, relationships, and living establishment) immediately after drug intake. In humans, some of the aversive consequences related to drug use occur during drug seeking, such as hiding from law enforcement, family, and friends, or securing the funds to obtain the drug. Therefore, human drug-seeking episodes during abstinence often involve a “conflict” situation, which usually involves a choice between pursuing the path that leads to experiencing the positive effects of drug(s) accompanied with aversive consequences and the path that avoids the aversive consequences of drug seeking (Epstein and Preston 2003; Cooper et al. 2007). In this case, the aversive consequences are not contingent on the drug-taking response and therefore do not occur after drug intake, but instead are present during drug seeking and can occur before drug taking. Therefore, an abstinence “conflict” model where the aversive consequences occur during drug seeking would be useful in further characterizing the different aspects involved in human drug abstinence. Further, greater construct validity could be achieved with an abstinence “conflict” model that presents the negative consequences during drug seeking and not as a punishment contingent on the drug-taking response. Abstinence “conflict” model Cooper et al. (2007) developed a conflict-based abstinence model where the negative consequences occur during cocaine seeking. This model was based on an earlier model that used the “Columbia Obstruction Box” method, which assessed rats’ motivation for rewards under different deprivation conditions, while in the presence of an electric barrier (Jenkins et al. 1926). Typically in the abstinence conflict model, rats are trained to lever press for drug infusions paired with a discrete light stimulus. An electric barrier is then introduced by

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electrifying the floor area near the levers, while the drug continues to be available; thus, the animals can continue to self-administer drug but doing so necessitates enduring electric shock BEFORE making the drug-taking response (lever press). Then the electric shock intensities are increased daily until the rats stop emitting the drug-taking (i.e., lever pressing) response, an outcome operationally defining abstinence (Cooper et al. 2007; Barnea-Ygael et al. 2012; Peck et al. 2013). The conflict model has important abstinence features that are not present in the other models described in this review. Further, it most closely represents the human abstinence condition of the aversive consequences that are present during drug seeking. That is, abstinence occurs because the drug’s rewarding effects are outweighed by the aversive consequences of drug seeking (Panlilio et al. 2003; Panlilio et al. 2005; Cooper et al. 2007; Barnea-Ygael et al. 2012). Further, the model demonstrates how the aversive consequences of drug seeking play an integral part in the initiation and maintenance of drug abstinence and perhaps, in the prevention of relapse. Thus, the abstinence conflict model has strong face and construct validities and might serve an important complementary role in drug abuse research by emphasizing features of human drug abstinence that are not emphasized by other models. The abstinence conflict model may be useful for studying the environmental and neural mechanisms underlying longterm abstinence in drug addiction (Saunders et al. 2013). For example, as discussed earlier in the review, the behavioral treatment strategies that employ not only positive consequences for remaining abstinent (e.g., environmental enrichment), but also aversive consequences for drug seeking (e.g., counterconditioning and contingency management) have been somewhat successful in supporting abstinence in humans. These important behavioral strategy features for abstinence must be taken into consideration when investigating the underlying mechanisms involved in what may lead to successful long-term abstinence in humans. Therefore, using the abstinence conflict model to investigate behavioral treatments could lead to more effective treatment outcomes for human addicts by bringing together both the positive consequences of abstinent behavior (e.g., enrichment) and the negative consequences of drug seeking (e.g., electric barrier). Thus, the abstinence conflict model seems suitable for further developing behavioral, environmental, and neurobiological (i.e., pharmacotherapeutic) strategies to support long-term drug abstinence in humans.

Conclusion To date, an enormous amount of resources has been devoted to developing pharmacotherapies for drug addiction, with relatively little or no long term success (Kreek et al. 2002; Koob

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et al. 2009). Consequently, it appears that strategies for treatment that focus solely on medication to alleviate some of the negative consequences of abstinence, such as withdrawal symptoms or craving, are not effective in sustaining longterm abstinence. It is argued that a successful drug-treatment program will be one that focuses on both the neural mechanisms within the addicted individual and the environmental contingencies that mediate drug use. Increasing our understanding about which behavioral factors determine successful long-term abstinence will lead to more effective behavioral treatment strategies that support long-term abstinence. When evaluating the behavioral treatment strategies previously discussed, we outlined the individual strengths that each behavioral strategy provides in the support of long-term drug abstinence. For example, a major strength of the contingency management strategy is its use of both positive consequences and negative consequences to support abstinence; a strength of the environmental enrichment approach is that it provides other forms of reinforcement that can reduce the attractiveness of drug-related stimuli, leading to greater support for abstinence. If used simultaneously, the important features that each behavioral treatment strategy employs might lead to an optimal behavioral approach that sustains long-term abstinence. Further, because the factors that support long-term drug abstinence in humans are similar to those in animals, the field might benefit from a greater use of animal models of drug abstinence that incorporate negative consequences for drug seeking and drug taking while the drug remains readily available. Thus, animal abstinence models that mimic human drug abstinence, such as the abstinence conflict model, could lead to a better understanding of the neurobiological, environmental, and behavioral factors that support long-term abstinence. This may lead to an increasing need for “back translational” approaches where clinical treatment strategies that support long-term drug abstinence in humans begin to consider aligning themselves with the well-controlled and validated animal abstinence and relapse models. In turn, this could both inform and aid in the development of more effective behavi o r a l , e n v i r o n m e n t a l , a n d ne u r o b i o l o g i c a l ( i . e . , pharmacotherapeutic) interventions to treat drug addiction. Acknowledgements We thank Dr. Bruce Brown and Dr. Bertram Ploog for critical comments on earlier versions of this paper. Conflicts of interest The authors declare no conflicts of interests.

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