More than 85% of people who give up an addictive drug begin using it again within a year. Relapse rates have changed little over the past five decades. Situations, places and objects associated with drug-taking can trigger relapse long after a person’s last exposure to a drug.

We can study relapse by training animals to self-administer drugs such as cocaine. For example, rats can learn to press a lever to receive an infusion of a drug paired with a cue (a conditioned stimulus), such as a tone or a light. After training, the rats continue to press the lever to seek the drug, even if this behavior no longer delivers it. In addition, their lever pressing in response to cues increases with time for several months after their last drug exposure. This phenomenon, known as incubation of drug craving, mirrors the increase in cravings reported by abstinent drug users.

In drug users, cues such as the crack pipe or syringe used to take the drug can later contribute to drug relapse during abstinence. Most studies modeling this phenomenon have focused on how the rats respond to a conditioned stimulus that signaled the delivery of a drug during training. However, a second type of signal, known as the discriminative stimulus, can also influence relapse. Discriminative stimuli are sets of cues that signal whether drugs are about to become available or not; for example, the presence of people selling drugs on a street corner as opposed to the presence of police.

Madangopal et al. now show that discriminative stimuli – in the absence of conditioned stimuli – can also control the incubation of drug craving. Rats learned to press a lever in response to a light signaling the availability of cocaine (the positive discriminative stimulus), and to avoid responding to a different light indicating that cocaine was unavailable (the negative discriminative stimulus). When tested during abstinence, the rats only increased their lever pressing to the first light over time, i.e., they showed an incubation of drug craving controlled by the positive discriminative stimulus. Lever pressing peaked after 60 days of abstinence and persisted for up to 300 days (almost half the rats' lifespan). By contrast, the same discriminative stimuli did not trigger increased lever pressing when used to signal the availability of a palatable food.

Discriminative stimuli are thus powerful and persistent triggers of craving for addictive drugs. They signal the availability of a drug prior to both drug-taking and relapse, making them a critical target for intervention strategies. Understanding the mechanisms by which discriminative stimuli promote drug craving could lead to new treatments to prevent relapse.

The risk of relapse is a major obstacle for effective treatment of drug addiction (O'Brien, 2005; Wikler, 1973). In abstinent drug users, several factors contribute to drug relapse, including exposure to cues and contexts previously associated with drug use (O'Brien et al., 1992), stressors (Sinha, 2001), or acute exposure to the drug itself (Jaffe et al., 1989). Preclinical studies have recapitulated these effects in relapse models using mice, rats, and nonhuman primates (Venniro et al., 2016; Weiss, 2010). A major finding across these studies is that cue-induced drug-seeking (in the absence of the drug) increases progressively during abstinence, a phenomenon termed incubation of drug craving (Grimm et al., 2001; Neisewander et al., 2000). Time-dependent increases in drug-seeking have been demonstrated in cocaine (Lu et al., 2004a), heroin (Shalev et al., 2001), methamphetamine (Shepard et al., 2004), alcohol (Bienkowski et al., 2004), and nicotine (Abdolahi et al., 2010), as well as non-drug rewards such as sucrose (Grimm et al., 2002). These findings in rodents mirror incubation of cue-induced drug craving and physiological responses in human addicts (Bedi et al., 2011; Li et al., 2015a; Wang et al., 2013; Parvaz et al., 2016), and have been important for studying neural mechanisms contributing to drug relapse (Dong et al., 2017; Marchant et al., 2013; Pickens et al., 2011; Wolf, 2016).

Preclinical incubation models have shown how cues presented after performance of a drug-taking response and paired with subsequent drug delivery during training potentiate drug-seeking when presented response-contingently during abstinence. These ‘confirmatory’ conditioned stimuli (CSs) inform the laboratory animal that the drug-taking response has been completed during training. Early preclinical studies of incubation showed that it could also occur in the absence of such discrete drug-paired CSs (Lu et al., 2004a; Grimm et al., 2002). This suggests that incubation could also be induced by other stimuli associated with drug-taking, such as the contextual cues (e.g. the chamber used for operant training) or discriminative stimuli (DSs) that signal drug availability (e.g. the house-light that is illuminated during the training session, the retractable lever that serves as the operant manipulandum). Surprisingly, little is known about the factors underlying incubation in the absence of previously drug-paired CSs. A recent study suggested that it is not mediated by contextual cues (Adhikary et al., 2017), leaving DSs as a likely culprit. DSs are different from cues typically investigated in these studies in that they are neither response-contingent like CSs, nor ever-present like contextual cues. Rather, DSs signal drug availability—or unavailability—thereby preceding and guiding the performance of drug-taking behavior. Previous studies have shown that a DS signaling drug availability (DS+) can promote persistent drug-seeking behavior while a DS signaling drug unavailability (DS-) can inhibit drug-taking behavior and drug-priming-induced reinstatement of drug seeking (Weiss, 2010; Ettenberg, 1990; Gutman et al., 2017; Katner et al., 1999; McFarland and Ettenberg, 1997; Mihindou et al., 2013; Yun and Fields, 2003; Pitchers et al., 2017). Further, DS control of drug seeking persists for many months and is highly resistant to extinction (Ciccocioppo et al., 2004; Ghitza et al., 2003; Martin-Fardon and Weiss, 2017). Despite the importance of DSs in stimulus control of drug taking and relapse, it is unknown whether DS-controlled drug-seeking incubates during abstinence.

In this study, we sought to directly assess the contribution of DSs to incubation, in the absence of drug-paired CSs. To this end, we first designed a trial-based procedure to train male and female rats to discriminatively self-administer cocaine (0.75 mg/kg/infusion) during trials in which a DS+ signaled cocaine availability, and to suppress responding on the same lever during trials in which a DS- signaled cocaine unavailability during the same session. Drug infusions were not paired with CSs. We then tested for the ability of DSs to control cocaine seeking at multiple time points extending up to 400 days of abstinence. Further, after complete cessation of cocaine-seeking behavior, we assessed whether a priming dose of cocaine would reinstate DS-controlled cocaine seeking in the same rats. Finally, to determine whether DS-controlled incubation under our experimental conditions was specific to cocaine, we trained a separate group of rats on an analogous procedure using palatable food (45 mg high-carbohydrate pellets) as the operant reward and assessed the time course of DS-controlled food seeking.

We used a trial-based procedure to investigate incubation of cocaine or palatable-food seeking controlled by discriminative stimuli that signal availability (DS+) or unavailability (DS-) of the rewards in the absence of reward-paired CSs. Rats readily learned to respond to the DS+ for either cocaine (Experiment 1) or food (Experiment 2) and to inhibit responding to the DS- within the same session. DS-controlled cocaine seeking was maximal after 60 days of abstinence (reflecting incubation of DS-controlled cocaine seeking) and persisted for up to 300 days. Additionally, when DS-controlled cocaine seeking was fully extinguished after 400 days of abstinence, priming injections of cocaine reinstated cocaine seeking. In contrast, DS-controlled food seeking was maximal at 1 day of abstinence, progressively decreased over time, and was no longer observed after 60 abstinence days. Thus, incubation of DS-controlled reward seeking under our experimental conditions was specific for cocaine.

In previous studies, DSs paired with cocaine self-administration have been shown to promote drug seeking that is highly resistant to extinction across multiple non-reinforced test sessions (Ciccocioppo et al., 2004; Martin-Fardon and Weiss, 2017; Weiss et al., 2000). Reward deliveries in these studies were paired with additional discrete CSs, and the contrasting DSs were paired with different levers and presented in separate sessions, making it difficult to disentangle the potential contribution of DSs from CSs and contextual stimuli. In our experiments, reward deliveries were not paired with additional CSs during training, and the two contrasting DSs were paired with a common retractable lever and presented in a pseudorandomized order within the same session. Following training, the rats were tested under non-reinforced conditions for DS-controlled drug seeking, using the same DS presentation schedule as during training. Because the same operant manipulandum and response was required to seek reinforcement in response to each DS within the same test session, we know that discriminated drug seeking in our model was exclusively controlled by the DSs and not by contextual stimuli, classically conditioned spatial cues, presentation of the operant manipulandum, or even performance of the drug-seeking response. Under these conditions, we observed persistent non-reinforced drug seeking during DS+ presentations but not DS- presentations, up to 300 days after the last DS-drug pairing. These data extend previous studies of DS-controlled drug-seeking and suggest that in addition to setting the occasion for drug-seeking behavior, the DS+ is sufficient to motivate drug-seeking in the absence of explicit drug-paired CSs.

It has long been appreciated in basic behavioral research that learning about operant DSs involves both classical and operant conditioning (Mowrer, 1960; Rescorla and Solomon, 1967; Weiss, 1978; Weiss, 2014). As explained by Rescorla and Solomon (1967), all conditions necessary for classical conditioning are present during discriminated operant responding. Thus, in addition to setting the occasion for reward-taking it should be expected that a DS+ will come to elicit classically conditioned responses (CRs). Such CRs can include the induction of motivational states (i.e. drug craving). In the present study, rats learned to lever press during the DS+ for cocaine (i.e. they learned a stimulus-response-outcome relation and their behavior came under stimulus control). Because they received cocaine only during the DS+, they should have also learned a Pavlovian stimulus-outcome relation that would imbue the DS+ with incentive motivational properties (Weiss, 2014). These excitatory motivational properties, acquired through Pavlovian processes, likely contributed to the incubation effect observed in this study.

We demonstrate that DS-controlled cocaine seeking is potentiated during abstinence (that is, we show incubation of DS-controlled cocaine craving) even in the absence of explicit drug-paired CSs. Incubation studies have typically employed between-subjects testing procedures in which rats previously trained to self-administer an addictive drug are returned to the same chambers after varying periods of abstinence and tested for drug-seeking with or without the previously drug-paired CSs (Pickens et al., 2011; Li et al., 2015b; Lu et al., 2004b). Following cocaine self-administration, the response to cocaine-paired CSs progressively increased (‘incubated’) over the first 60–90 days of withdrawal (Grimm et al., 2001; Grimm et al., 2003). However, incubation has also been observed in the absence of drug-paired CSs; extinction responding in the absence of the drug-paired CSs also progressively increased for up to 90 days (Grimm et al., 2003) and persisted up to 180 days (Lu et al., 2004a). A recent study demonstrated that this potentiation is not mediated by contextual cues (Adhikary et al., 2017). However, the factors controlling incubation in the absence of previously drug-paired CSs were not elucidated. In the present study, we found a time-dependent increase in drug seeking (incubation) during DS+ presentations in the absence of any explicit drug-paired CSs during abstinence. DS-controlled seeking continued to increase up to 60 days into abstinence and persist up to 300 days (about half the lifespan of a rat). This time course of DS-controlled cocaine-seeking is especially remarkable when considering that the same group of rats were exposed to repeated relapse tests under extinction conditions. It is possible that in a between-subjects design, DS-controlled incubation would show a longer rise phase than the one observed here and persist beyond 300 days, in the absence of extinction learning over repeated relapse tests.

In contrast, cocaine seeking in DS- trials did not incubate – rats continued to suppress responding in DS- trials during all relapse tests and maintained discrimination up to 300 days of abstinence. DSs signaling cocaine unavailability have been shown to inhibit ongoing cocaine self-administration and to suppress cocaine priming-induced reinstatement (Mihindou et al., 2013). From the perspective of translation and treatment development, the inhibition of cocaine seeking may be just as important as its potentiation. The behavior guided by each DS in our study was able to survive multiple extinction sessions and subsequent tests of cocaine priming-induced reinstatement – after DS+ responding was extinguished to DS- levels – priming injections of cocaine reinstated cocaine seeking specifically during DS+, but not DS-, trials. Future studies with this procedure will dissociate the neurobiological mechanisms that allow these two functionally orthogonal DSs to mediate incubation of DS-controlled cocaine seeking.

Using a similar format of DS and lever presentation, we also trained rats to lever press for palatable food reward during DS+, but not DS-, trials. We found that food-DS rats made more total responses than cocaine-DS rats during training, maintained their discrimination responding under non-reinforced conditions, and also showed higher seeking responses than cocaine-DS rats during the initial relapse test on day 1. However, under the same repeated-testing schedule used for cocaine relapse, they quickly extinguished their DS-controlled responding in the absence of food and progressively decreased food seeking during abstinence. It is possible that DS-controlled food seeking would have incubated in the absence of repeated relapse testing in extinction. Indeed, incubation has been observed using the classical procedure with oral sucrose reward; sucrose reward-seeking during presentation of the previously reward-paired CSs (cue-induced reinstatement) progressively increased during abstinence, peaked at 30 days and abated at 90 days of abstinence (Lu et al., 2004b; Grimm et al., 2003). It is unlikely that the differences in non-drug seeking in response to CSs and DSs are the result of the choice of non-drug reinforcer as a recent study demonstrated incubation of CS-induced reward seeking using the same palatable food pellets (Krasnova et al., 2014). The greater persistence of seeking in response to drug- over food-DSs observed here is more likely a result of an inherent difference in the strength of stimulus-control exerted by drug- over food-DSs. Our findings are in agreement with earlier studies directly comparing drug and food paired-DSs (Ciccocioppo et al., 2004; Martin-Fardon and Weiss, 2017) but also more broadly, with studies comparing drug- and food-paired CSs (Tunstall and Kearns, 2016; N. Kearns et al., 2011). Future studies are required to determine whether this divergence of DS effects on drug versus food seeking is due to differences in the strength of the initial DS-reward associations during training or due to drug-specific neuroadaptations that emerge during abstinence (Wolf, 2016; Grimm et al., 2003; Shaham and Hope, 2005).

Taken together, the results of the present experiments show that DS-controlled operant drug seeking incubates during prolonged abstinence and persists up to 300 days of abstinence despite repeated relapse testing. However, using a similar repeated testing procedure, we observed an abatement of DS-controlled palatable food seeking. As we noted above, DS-controlled behaviors offer an especially promising path to treatment development because DSs are always present before and during human drug taking; they do not merely accompany or follow it. They can play a critical role in relapse; for example, a study measuring flight attendants’ cigarette craving showed that craving peaked toward the end of flights as the opportunity to smoke a cigarette neared, regardless of flight duration or time since the last cigarette (Dar et al., 2010). Animal models of other aspects of addictive behavior have been questioned, by us and other authors, because the timing or sequencing of events does not reflect the typical experiences of human drug users (Epstein and Kowalczyk, 2018; Vanderschuren et al., 2017). The procedure we describe here addresses those concerns in the realm of cue reactivity and its incubation, and is well suited to disentangle the complex array of behavioral and neural mechanisms underlying the contributions of DSs to relapse (Bradfield and Balleine, 2013; Colwill and Rescorla, 1990; Rescorla, 1990; de Wit and Dickinson, 2009).

All data generated or analyzed during this study, and needed to evaluate the conclusions in the paper, are included in the manuscript and supplementary materials.

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Author details

1. Rajtarun Madangopal

   Neuronal Ensembles in Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6202-302X

2. Brendan J Tunstall

   Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

3. Lauren E Komer

   Neuronal Ensembles in Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

   Present address

   Graduate School of Medical Sciences, Weill Cornell Medicine, New York, United States

   Contribution

   Data curation, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

4. Sophia J Weber

   Neuronal Ensembles in Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

   Contribution

   Data curation, Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

5. Jennifer K Hoots

   Neurobiology of Relapse Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

   Present address

   Department of Psychology, University of Illinois at Chicago, Chicago, United States

   Contribution

   Data curation, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

6. Veronica A Lennon

   Neuronal Ensembles in Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

   Contribution

   Data curation, Writing—review and editing

   Competing interests

   No competing interests declared

7. Jennifer M Bossert

   Neurobiology of Relapse Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

   Contribution

   Conceptualization, Resources, Supervision, Investigation, Methodology, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

8. David H Epstein

   Real-world Assessment, Prediction, and Treatment Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

   Contribution

   Formal analysis, Supervision, Writing—review and editing

   Competing interests

   No competing interests declared

9. Yavin Shaham

   Neurobiology of Relapse Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

   Contribution

   Conceptualization, Resources, Supervision, Methodology, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

10. Bruce T Hope

    Neuronal Ensembles in Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

    For correspondence

    bhope@intra.nida.nih.gov

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5804-7061

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