Abstinence as Choice: Exploring Voluntary Abstinence from Alcohol Self-Administration Using the Resurgence-as-Choice Framework.

Resurgence is an increase in the rate of a previously suppressed behavior that occurs when an alternative source of reinforcement is made worse in some way. The Resurgence as Choice model offers a quantitative approach to understanding resurgence that may provide important insights into the variables that affect this form of relapse in the natural environment. Bringing this model to bear on relapse following reinforcement-based interventions for alcohol and other substance use disorders, however, may not be straightforward. Laboratory work on which the Resurgence as Choice model is based has almost exclusively focused on resurgence following extinction of target behavior, but abstinence from alcohol during intervention is often voluntary: Patients may drink alcohol and forfeit therapeutic reinforcers at any time. In this article, we first will review recent data from our group that demonstrate a method for studying resurgence following voluntary abstinence from alcohol seeking in rats. In a previous experiment, we reduced rats' alcohol-maintained lever pressing to low levels without placing it on extinction by arranging nondrug differential reinforcement of other behavior. Further, when we suspended nondrug reinforcement, resurgence of lever pressing occurred. Next, we will explore methods for modeling these outcomes using the Resurgence-as-Choice framework. We conclude that the data under consideration may not be sufficient to discriminate between candidate models of resurgence following voluntary abstinence and point to areas for future empirical and theoretical development. This work may provide a stronger bridge between preclinical and conceptual work on resurgence and clinical treatments for alcohol use disorder.

Resurgence of ethanol seeking following voluntary abstinence produced by nondrug differential reinforcement of other behavior.

Resurgence refers to the relapse of a target behavior following the worsening of a source of alternative reinforcement that was made available during response elimination. Most laboratory analyses of resurgence have used a combination of extinction and alternative reinforcement to reduce target behavior. In contingency-management treatments for alcohol use disorder, however, alcohol use is not placed on extinction. Instead, participants voluntarily abstain from alcohol use to access nondrug alternative reinforcers. Inasmuch, additional laboratory research on resurgence following voluntary abstinence is warranted. The present experiment evaluated resurgence of rats' ethanol seeking following voluntary abstinence produced by differential reinforcement of other behavior (DRO). Lever pressing produced ethanol reinforcers during baseline phases. During DRO phases, lever pressing continued to produce ethanol and food reinforcers were delivered according to resetting DRO schedules. Ethanol and food reinforcers were suspended during resurgence test phases to evaluate resurgence following voluntary abstinence. Lever pressing was elevated during baseline phases and occurred at near-zero rates during DRO phases. During the resurgence test phases, lever pressing increased, despite that it no longer produced ethanol. The procedure introduced here may help researchers better understand the variables that affect voluntary abstinence from ethanol seeking and resurgence following voluntary abstinence.

Increased heroin intake and relapse vulnerability in intermittent relative to continuous self-administration: Sex differences in rats.

BACKGROUND AND PURPOSE: Studies using intermittent-access drug self-administration show increased motivation to take and seek cocaine and fentanyl, relative to continuous access. In this study, we examined the effects of intermittent- and continuous-access self-administration on heroin intake, patterns of self-administration and cue-induced heroin-seeking, after forced or voluntary abstinence, in male and female rats. We also modelled brain levels of heroin and its active metabolites. EXPERIMENTAL APPROACH: Rats were trained to self-administer a palatable solution and then heroin (0.075 mg·kg-1 per inf) either continuously (6 h·day-1 ; 10 days) or intermittently (6 h·day-1 ; 5-min access every 30-min; 10 days). Brain levels of heroin and its metabolites were modelled using a pharmacokinetic software. Next, heroin-seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The oestrous cycle was measured using a vaginal smear test. KEY RESULTS: Intermittent access exacerbated heroin self-administration and was characterized by a burst-like intake, yielding higher brain peaks of heroin and 6-monoacetylmorphine concentrations. Moreover, intermittent access increased cue-induced heroin-seeking during early, but not late abstinence. Heroin-seeking was higher in females after intermittent, but not continuous access, and this effect was independent of the oestrous cycle. CONCLUSIONS AND IMPLICATIONS: Intermittent heroin access in rats resembles critical features of heroin use disorder: a self-administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Acute food deprivation-induced relapse to heroin seeking after short and long punishment-imposed abstinence in male rats.

RATIONAL: Stress is a major trigger for drug relapse in humans and animal models, even after prolonged abstinence. However, animal models for stress-induced relapse were criticized for the lack of predictive and face validity. OBJECTIVES: Here we investigated the effect of acute food deprivation stress in a novel stress-induced relapse model using voluntary, punishment-imposed abstinence from heroin. We also performed a detailed characterization of the development of punishment-imposed abstinence. METHODS: Male rats were trained to self-administered heroin (0.1 mg/kg/infusion) for 2 weeks, using the seeking-taking chained schedule. Pressing the 'seeking' lever led to the insertion of the 'taking' lever and pressing the take lever resulted in heroin infusion. Following self-administration training, rats were exposed to 8 or 21 days of heroin-seeking punishment. During punishment, 30% of the completed seek links resulted in a mild escalating footshock instead of take lever presentation. Next, rats were tested for heroin seeking under extinction conditions after 24 h of food deprivation and sated conditions. RESULTS: Probabilistic punishment of seeking lever responses resulted in gradual suppression of heroin seeking and taking. Exposure to food-deprivation stress induced a robust relapse to heroin seeking after short and long punishment-imposed abstinence periods, without significant effects of time, i.e., no incubation of heroin seeking. Individual differences were observed in the development of punishment-induced abstinence and stress-induced relapse. CONCLUSIONS: These results suggest that stress is a reliable trigger to relapse even after a prolonged period of punishment-induced, voluntary abstinence.

Orbitofrontal cortex and dorsal striatum functional connectivity predicts incubation of opioid craving after voluntary abstinence.

We recently introduced a rat model of incubation of opioid craving after voluntary abstinence induced by negative consequences of drug seeking. Here, we used resting-state functional MRI to determine whether longitudinal functional connectivity changes in orbitofrontal cortex (OFC) circuits predict incubation of opioid craving after voluntary abstinence. We trained rats to self-administer for 14 d either intravenous oxycodone or palatable food. After 3 d, we introduced an electric barrier for 12 d that caused cessation of reward self-administration. We tested the rats for oxycodone or food seeking under extinction conditions immediately after self-administration training (early abstinence) and after electric barrier exposure (late abstinence). We imaged their brains before self-administration and during early and late abstinence. We analyzed changes in OFC functional connectivity induced by reward self-administration and electric barrier-induced abstinence. Oxycodone seeking was greater during late than early abstinence (incubation of oxycodone craving). Oxycodone self-administration experience increased OFC functional connectivity with dorsal striatum and related circuits that was positively correlated with incubated oxycodone seeking. In contrast, electric barrier-induced abstinence decreased OFC functional connectivity with dorsal striatum and related circuits that was negatively correlated with incubated oxycodone seeking. Food seeking was greater during early than late abstinence (abatement of food craving). Food self-administration experience and electric barrier-induced abstinence decreased or maintained functional connectivity in these circuits that were not correlated with abated food seeking. Opposing functional connectivity changes in OFC with dorsal striatum and related circuits induced by opioid self-administration versus voluntary abstinence predicted individual differences in incubation of opioid craving.

Abstinence-dependent dissociable central amygdala microcircuits control drug craving.

We recently reported that social choice-induced voluntary abstinence prevents incubation of methamphetamine craving in rats. This inhibitory effect was associated with activation of protein kinase-Cδ (PKCδ)-expressing neurons in central amygdala lateral division (CeL). In contrast, incubation of craving after forced abstinence was associated with activation of CeL-expressing somatostatin (SOM) neurons. Here we determined the causal role of CeL PKCδ and SOM in incubation using short-hairpin RNAs against PKCδ or SOM that we developed and validated. We injected two groups with shPKCδ or shCtrlPKCδ into CeL and trained them to lever press for social interaction (6 d) and then for methamphetamine infusions (12 d). We injected two other groups with shSOM or shCtrlSOM into CeL and trained them to lever press for methamphetamine infusions (12 d). We then assessed relapse to methamphetamine seeking after 1 and 15 abstinence days. Between tests, the rats underwent either social choice-induced abstinence (shPKCδ groups) or homecage forced abstinence (shSOM groups). After test day 15, we assessed PKCδ and SOM, Fos, and double-labeled expression in CeL and central amygdala medial division (CeM). shPKCδ CeL injections decreased Fos in CeL PKCδ-expressing neurons, increased Fos in CeM output neurons, and reversed the inhibitory effect of social choice-induced abstinence on incubated drug seeking on day 15. In contrast, shSOM CeL injections decreased Fos in CeL SOM-expressing neurons, decreased Fos in CeM output neurons, and decreased incubated drug seeking after 15 forced abstinence days. Our results identify dissociable central amygdala mechanisms of abstinence-dependent expression or inhibition of incubation of craving.

Operant Social Reward Decreases Incubation of Heroin Craving in Male and Female Rats.

BACKGROUND: We recently reported that operant social choice-induced voluntary abstinence prevents incubation of methamphetamine craving. Here, we determined whether social choice-induced voluntary abstinence would prevent incubation of heroin craving. We also introduce a fully automatic social reward self-administration model that eliminates the intense workload and rat-human interaction of the original semiautomatic model. METHODS: In experiment 1, we trained male and female rats for social self-administration (6 days) and then for heroin self-administration (12 days). Next, we assessed relapse to heroin seeking after 1 and 15 abstinence days. Between tests, the rats underwent either forced or social choice-induced abstinence. In experiment 2, we developed a fully automatic social self-administration procedure by introducing a screen between the self-administration chamber and the social-peer chamber; the screen allows physical contact but prevents rats from crossing chambers. Next, we compared incubation of craving in rats with a history of standard (no-screen) or automatic (screen) social self-administration and social choice-induced abstinence. RESULTS: The time-dependent increase in heroin seeking after cessation of drug self-administration (incubation of craving) was lower after social choice-induced abstinence than after forced abstinence. There were no differences in social self-administration, social choice-induced abstinence, and incubation of craving in rats trained in the standard semiautomatic procedure versus the novel fully automatic procedure. CONCLUSIONS: Our study demonstrates the protective effect of rewarding social interaction on heroin self-administration and incubation of heroin craving and introduces a fully automatic social self-administration and choice procedure to investigate the role of volitional social interaction in drug addiction and other psychiatric disorders.

Modeling cocaine relapse in rodents: Behavioral considerations and circuit mechanisms.

Addiction is a chronic relapsing disorder, in that most addicted individuals who choose to quit taking drugs fail to maintain abstinence in the long-term. Relapse is especially likely when recovering addicts encounter risk factors like small "priming" doses of drug, stress, or drug-associated cues and locations. In rodents, these same factors reinstate cocaine seeking after a period of abstinence, and extensive preclinical work has used priming, stress, or cue reinstatement models to uncover brain circuits underlying cocaine reinstatement. Here, we review common rat models of cocaine relapse, and discuss how specific features of each model influence the neural circuits recruited during reinstated drug seeking. To illustrate this point, we highlight the surprisingly specific roles played by ventral pallidum subcircuits in cocaine seeking reinstated by either cocaine-associated cues, or cocaine itself. One goal of such studies is to identify, and eventually to reverse the specific circuit activity that underlies the inability of some humans to control their drug use. Based on preclinical findings, we posit that circuit activity in humans also differs based on the triggers that precipitate craving and relapse, and that associated neural responses could help predict the triggers most likely to elicit relapse in a given person. If so, examining circuit activity could facilitate diagnosis of subgroups of addicted people, allowing individualized treatment based on the most problematic risk factors.

Role of Dorsomedial Striatum Neuronal Ensembles in Incubation of Methamphetamine Craving after Voluntary Abstinence.

We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence (using a discrete choice procedure between methamphetamine and food; 20 trials/d) for 19 d. We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization colabeling results, we tested the causal role of DMS D1 and D2 family receptors, and DMS neuronal ensembles in "incubated" methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively. Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of methamphetamine craving). The incubated response was associated with increased Fos expression in DMS but not in DLS; Fos was colabeled with both Drd1 and Drd2 DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMS on abstinence day 18 decreased incubated methamphetamine seeking on day 21. Results demonstrate a role of DMS dopamine D1 and D2 receptors in the incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation. SIGNIFICANCE STATEMENT: In human addicts, abstinence is often self-imposed and relapse can be triggered by exposure to drug-associated cues that induce drug craving. We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we used classical pharmacology, in situ hybridization, immunohistochemistry, and the Daun02 inactivation procedure to demonstrate a critical role of dorsomedial striatum neuronal ensembles in this new form of incubation of drug craving.

Animal models of drug relapse and craving: From drug priming-induced reinstatement to incubation of craving after voluntary abstinence.

High rates of relapse to drug use during abstinence is a defining feature of drug addiction. In abstinent drug users, drug relapse is often precipitated by acute exposure to the self-administered drug, drug-associated cues, stress, as well as by short-term and protracted withdrawal symptoms. In this review, we discuss different animal models that have been used to study behavioral and neuropharmacological mechanisms of these relapse-related phenomena. In the first part, we discuss relapse models in which abstinence is achieved through extinction training, including the established reinstatement model, as well as the reacquisition and resurgence models. In the second part, we discuss recent animal models in which drug relapse is assessed after either forced abstinence (e.g., the incubation of drug craving model) or voluntary (self-imposed) abstinence achieved either by introducing adverse consequences to ongoing drug self-administration (e.g., punishment) or by an alternative nondrug reward using a discrete choice (drug vs. palatable food) procedure. We conclude by briefly discussing the potential implications of the recent developments of animal models of drug relapse after voluntary abstinence to the development of medications for relapse prevention.