Animal Models of Drug Relapse and Craving after Voluntary Abstinence: A Review

Fredriksson, Ida; Vènniro, Marco; Reiner, David J.; Chow, Jonathan J.; Bossert, Jennifer M.; Shaham, Yavin

doi:10.1124/pharmrev.120.000191

Cited by 74 publications

(47 citation statements)

References 160 publications

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“…These results agree with those from our previous study with oxycodone in which we did not observe sex differences in extinction responding, context-induced reinstatement and reacquisition (Bossert et al, 2020), and other studies using the extinction-reinstatement procedure showed similar magnitude of reinstatement of opioid seeking in males and female rats (Nicolas et al, 2021). Our negative sex differences data also agree with those from our recent studies on relapse to opioid seeking after voluntary abstinence induced by either providing rats with alternative rewards (palatable food or social interaction) in a choice procedure or exposing them to an electric barrier near the drug-paired lever (Fredriksson et al, 2020(Fredriksson et al, , 2021Reiner et al, 2020;Venniro et al, 2017Venniro et al, , 2019.…”

Section: Dissociable Effects Of Bu08028 On Different Relapse-related ...supporting

confidence: 90%

“…Together, the results from the present study and our previous studies with oxycodone (Bossert et al, 2020; Fredriksson et al, 2020) highlight the importance of including both sexes in studies aimed at identifying novel medications for relapse prevention in animal models because even under conditions where the relapse‐related behaviour is similar in males and females, the response to the target medications can be sex‐specific (Fredriksson et al, 2021).…”

Section: Discussionsupporting

confidence: 72%

“…We also added to our experimental procedure an assessment of BU08028's effect on incubation of heroin craving (Shalev et al, 2001; Theberge et al, 2013). Incubation of drug craving refers to the time‐dependent increases in drug seeking during abstinence (Fredriksson et al, 2021; Grimm et al, 2001). Finally, we assessed BU08028's effect on heroin versus food choice in a rat model in which the choice for intravenous opioid agonists progressively increases with increasing the drugs' unit dose (Townsend et al, 2021; Townsend, Negus, et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance

Bossert

Townsend

Altidor

et al. 2021

British J Pharmacology

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Background and Purpose Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modelled maintenance treatment in rats and found that chronic delivery of buprenorphine or the μ opioid receptor partial agonist TRV130 decreased relapse to oxycodone seeking and taking. Here, we tested the buprenorphine analogue BU08028 on different heroin relapse‐related measures and heroin versus food choice. Experimental Approach For relapse assessment, we trained male and female rats to self‐administer heroin (6 h·day−1, 14 days) in Context A and then implanted osmotic minipumps containing BU08028 (0, 0.03 or 0.1 mg·kg−1·d−1). Effects of chronic BU08028 delivery were tested on (1) incubation of heroin‐seeking in a non‐drug Context B, (2) extinction responding reinforced by heroin‐associated discrete cues in Context B, (3) reinstatement of heroin‐seeking induced by re‐exposure to Context A and (4) re‐acquisition of heroin self‐administration in Context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin versus food choice. Key Results Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased re‐acquisition of heroin self‐administration selectively in females. Chronic BU08028 had minimal effects on context‐induced reinstatement and heroin versus food choice in both sexes. Finally, exploratory post hoc analyses suggest that BU08028 decreased extinction responding selectively in males. Conclusions and Implications Chronic BU08028 delivery had both beneficial and detrimental, sex‐dependent, effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 would not be an effective opioid maintenance treatment in humans.

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Section: Dissociable Effects Of Bu08028 On Different Relapse-related ...supporting

confidence: 90%

Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance

Bossert

Townsend

Altidor

et al. 2021

British J Pharmacology

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“…The reasons for the different results are unknown but may be due to procedural differences, including longer duration daily sessions (12 h per day in Venniro et al, 2018) and prior training to lever press for rewarding social interaction (Venniro et al, 2018) before cocaine self-administration in Venniro et al (2021). Based on previous reports showing the protective effect of social reward on drug seeking and craving (Solinas et al, 2008;Venniro et al, 2018;Fredriksson et al, 2021), prior social interaction with a peer during the social self-administration phase may have decreased cocaine craving after intermittent access cocaine selfadministration.…”

Section: Incubation Of Craving and Progressive Ratio Responding After...mentioning

confidence: 99%

Dissociation Between Incubation of Cocaine Craving and Anxiety-Related Behaviors After Continuous and Intermittent Access Self-Administration

et al. 2022

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Studies using either continuous or intermittent access cocaine self-administration procedures showed that cocaine seeking increases during abstinence (incubation of cocaine craving), and that this effect is higher after intermittent cocaine access. Other studies showed that cocaine abstinence is characterized by the emergence of stress- and anxiety-related states which were hypothesized to increase relapse vulnerability. We examined whether incubation of cocaine craving and anxiety-related behaviors are correlated and whether intermittent cocaine self-administration would potentiate these behaviors during abstinence. Male rats self-administered cocaine either continuously (6 h/day) or intermittently (5 min ON, 25 min OFF × 12) for 14 days, followed by relapse tests after 1 or 21 abstinence days. A group of rats that self-administered saline served as a control. Anxiety-related behaviors were measured on the same abstinence days, using the novelty induced-hypophagia test. Finally, motivation for cocaine was measured using a progressive ratio reinforcement schedule. Lever-presses after 21 abstinence days were higher than after 1 day and this incubation effect was higher in the intermittent access group. Progressive ratio responding was also higher after intermittent cocaine access. Intermittent and continuous cocaine access did not induce anxiety-like responses in the novelty-induced hypophagia test after 1 or 21 abstinence days. Independent of the access condition, incubation of cocaine seeking was not correlated with the novelty-induced hypophagia measures. Results suggest that cocaine-induced anxiety-related states during protracted abstinence do not contribute to incubation of cocaine craving. However, this conclusion is tentative because we used a single anxiety-related measure and did not test female rats.

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“…Many prior rodent reinstatement studies have examined the brain substrates of opioid relapse following experimenter-imposed homecage abstinence (such as incubation of craving), or extinction training [9][10][11][12][13][14][15][16]. Fewer studies have used models in which rodents instead voluntarily cease their drug use, for example due to delivery of punishing shocks co-administered with drug.…”

Section: Introductionmentioning

confidence: 99%

Ventral pallidum GABA neurons bidirectionally control opioid relapse across rat behavioral models

Farrell

Xie

et al. 2022

Preprint

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Opioid addiction is a chronic, relapsing disorder. Whether addicted individuals are forced to abstain or they decide themselves to quit using drugs, relapse rates are high--especially upon encountering contexts and stimuli associated with prior opioid use. Rodents similarly show context- and cue-induced reinstatement of drug seeking following abstinence, and intriguingly, the neural circuits underlying these relapse-like behaviors differ when abstinence is involuntarily imposed, versus when animals decide themselves to cease taking drug. Here, we employ two complementary rat behavioral models of relapse-like behavior for the highly reinforcing opioid drug remifentanil, and asked whether GABAergic neurons in the ventral pallidum (VPGABA) control opioid seeking under these behavioral conditions. Specifically, we asked how chemogenetically stimulating VPGABA neurons with clozapine-N-oxide (CNO) influences the ability of contextual or discrete remifentanil-paired cues to reinstate drug seeking following either voluntary (punishment-induced; GroupPunish), or experimenter-imposed (extinction training; GroupExt) abstinence. In GroupPunish rats, we also chemogenetically inhibited VPGABA neurons, and examined spontaneous VP activity (Fos) during cued-reinstatement. In both GroupPunish and GroupExt rats, stimulating Gq-signaling in VPGABA neurons augmented remifentanil reinstatement in a cue- and context-dependent manner. Conversely, engaging inhibitory Gi-signaling in VPGABA neurons in GroupPunish suppressed cue-induced reinstatement, and additionally cue-triggered seeking was correlated with Fos in rostral, but not caudal VP. In contrast, neither stimulating nor inhibiting VPGABA neurons influenced unpunished remifentanil self-administration. We conclude that VPGABA neurons bidirectionally control opioid seeking regardless of the specific relapse model employed, highlighting their fundamental role in opioid relapse-like behavior across behavioral models, and potentially across species.

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Animal Models of Drug Relapse and Craving after Voluntary Abstinence: A Review

Cited by 74 publications

References 160 publications

Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance

Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance

Dissociation Between Incubation of Cocaine Craving and Anxiety-Related Behaviors After Continuous and Intermittent Access Self-Administration

Ventral pallidum GABA neurons bidirectionally control opioid relapse across rat behavioral models

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