Yavin Shaham, Ph.D.

@article{D’Ottavio2026,

title = {Brain metabolic correlates of heroin addiction severity during abstinence and heroin versus social seeking: a PET study in rats.},

author = {G D’Ottavio and A Sullivan and E Pilz and O Solis and I Schoenborn and J Gomez and T Kahnt and M Michaelides and Y Shaham},

year  = {2026},

date = {2026-07-30},

urldate = {2026-07-30},

journal = {Proceedings of the National Academy of Science (USA) - (in press)},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39933931b,

title = {The Role of Claustrum in Incubation of Opioid Seeking after Electric Barrier-Induced Voluntary Abstinence in Male and Female Rats},

author = {Kenichiro Negishi and Ying Duan and Ashley Batista and Mona S Pishgar and Pei-Jung Tsai and Kiera E Caldwell and Sarah M Claypool and David J Reiner and Rajtarun Madangopal and Jennifer M Bossert and Yihong Yang and Yavin Shaham and Ida Fredriksson},

url = {https://pubmed.ncbi.nlm.nih.gov/39933931/},

doi = {10.1523/JNEUROSCI.0561-24.2025},

issn = {1529-2401},

year  = {2025},

date = {2025-03-01},

urldate = {2025-03-01},

journal = {J Neurosci},

volume = {45},

number = {13},

abstract = {We previously reported that ventral subiculum (vSub) activity is critical to incubation of oxycodone seeking after abstinence induced by adverse consequences of drug seeking. Here, we studied the role of claustrum, a key vSub input, in this incubation. We trained male and female rats to self-administer oxycodone for 2 weeks and then induced abstinence by exposing them to an electric barrier for 2 weeks. We used retrograde tracing (cholera toxin B subunit) plus the activity marker Fos to identify projections to vSub cactivated during "incubated" relapse (Abstinence Day 15). We then used pharmacological reversible inactivation to determine the causal role of claustrum in incubation and the behavioral and anatomical specificity of this role. We also used an anatomical disconnection procedure to determine the causal role of claustrum-vSub connections in incubation. Finally, we analyzed an existing functional MRI dataset to determine if functional connectivity changes in claustrum-related circuits predict incubation of oxycodone seeking. Claustrum neurons projecting to vSub were activated during relapse tests after electric barrier-induced abstinence. Inactivation of claustrum but not areas dorsolateral to claustrum decreased incubation of oxycodone seeking after electric barrier-induced abstinence; claustrum inactivation had no effect on incubation after food choice-induced abstinence. Both ipsilateral and contralateral inactivation of claustrum-vSub projections decreased incubation after electric barrier-induced abstinence. Functional connectivity changes in claustrum-cortical circuits during electric barrier-induced abstinence predicted incubated oxycodone relapse. Our study identified a novel role of claustrum in relapse to opioid drugs after abstinence induced by adverse consequences of drug seeking.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36717230,

title = {Effect of Selective Lesions of Nucleus Accumbens µ-Opioid Receptor-Expressing Cells on Heroin Self-Administration in Male and Female Rats: A Study with Novel  Knock-in Rats},

author = {Jennifer M Bossert and Carlos A Mejias-Aponte and Thomas Saunders and Lindsay Altidor and Michael Emery and Ida Fredriksson and Ashley Batista and Sarah M Claypool and Kiera E Caldwell and David J Reiner and Jonathan J Chow and Matthew Foltz and Vivek Kumar and Audrey Seasholtz and Elizabeth Hughes and Wanda Filipiak and Brandon K Harvey and Christopher T Richie and Francois Vautier and Juan L Gomez and Michael Michaelides and Brigitte L Kieffer and Stanley J Watson and Huda Akil and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/36717230/},

doi = {10.1523/JNEUROSCI.2049-22.2023},

issn = {1529-2401},

year  = {2023},

date = {2023-03-01},

urldate = {2023-03-01},

journal = {J Neurosci},

volume = {43},

number = {10},

pages = {1692--1713},

abstract = {The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based  knock-in transgenic rat that provides cell type-specific genetic access to MOR-expressing cells. After performing anatomic and behavioral validation experiments, we used the  knock-in rats to study the involvement of NAc MOR-expressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and FISH chain reaction (HCR-FISH), we found no differences in  expression in NAc, dorsal striatum, and dorsal hippocampus, or MOR receptor density (except dorsal striatum) or function between  knock-in rats and wildtype littermates. HCR-FISH assay showed that  is highly coexpressed with  (95%-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells. We found that the lesions decreased acquisition of heroin self-administration in male  rats and had a stronger inhibitory effect on the effort to self-administer heroin in female  rats. The validation of an  knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study indicates that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in male and female rats. The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based  knock-in transgenic rat that provides cell type-specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the  knock-in rats to show that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in males and females. The new  rats can be used to study the role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36630511,

title = {Role of ventral subiculum neuronal ensembles in incubation of oxycodone craving after electric barrier-induced voluntary abstinence},

author = {Ida Fredriksson and Pei-Jung Tsai and Aniruddha Shekara and Ying Duan and Sarah V Applebey and Angelica Minier-Toribio and Ashley Batista and Jonathan J Chow and Lindsay Altidor and Estelle Barbier and Carlo Cifani and Xuan Li and David J Reiner and F Javier Rubio and Bruce T Hope and Yihong Yang and Jennifer M Bossert and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/36630511/},

doi = {10.1126/sciadv.add8687},

issn = {2375-2548},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {Sci Adv},

volume = {9},

number = {2},

pages = {eadd8687},

abstract = {High relapse rate is a key feature of opioid addiction. In humans, abstinence is often voluntary due to negative consequences of opioid seeking. To mimic this human condition, we recently introduced a rat model of incubation of oxycodone craving after electric barrier-induced voluntary abstinence. Incubation of drug craving refers to time-dependent increases in drug seeking after cessation of drug self-administration. Here, we used the activity marker Fos, muscimol-baclofen (GABAa + GABAb receptor agonists) global inactivation, Daun02-selective inactivation of putative relapse-associated neuronal ensembles, and fluorescence-activated cell sorting of Fos-positive cells and quantitative polymerase chain reaction to demonstrate a key role of vSub neuronal ensembles in incubation of oxycodone craving after voluntary abstinence, but not homecage forced abstinence. We also used a longitudinal functional magnetic resonance imaging method and showed that functional connectivity changes in vSub-related circuits predict opioid relapse after abstinence induced by adverse consequences of opioid seeking.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{doi:10.1073/pnas.2209382119,

title = {Incubation of palatable food craving is associated with brain-wide neuronal activation in mice},

author = {Rajtarun Madangopal and Eric R. Szelenyi and Joseph Nguyen and Megan B. Brenner and Olivia R. Drake and Diana Q. Pham and Aniruddha Shekara and Michelle Jin and Jia Jie Choong and Conor Heins and Lauren E. Komer and Sophia J. Weber and Bruce T. Hope and Yavin Shaham and Sam A. Golden},

url = {https://www.pnas.org/doi/abs/10.1073/pnas.2209382119},

doi = {10.1073/pnas.2209382119},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Proceedings of the National Academy of Sciences},

volume = {119},

number = {45},

pages = {e2209382119},

abstract = {Studies using rodent models have shown that relapse to drug or food seeking increases progressively during abstinence, a behavioral phenomenon termed ``incubation of craving.'' Mechanistic studies of incubation of craving have focused on specific neurobiological targets within preselected brain areas. Recent methodological advances in whole-brain immunohistochemistry, clearing, and imaging now allow unbiased brain-wide cellular resolution mapping of regions and circuits engaged during learned behaviors. However, these whole-brain imaging approaches were developed for mouse brains, while incubation of drug craving has primarily been studied in rats, and incubation of food craving has not been demonstrated in mice. Here, we established a mouse model of incubation of palatable food craving and examined food reward seeking after 1, 15, and 60 abstinence days. We then used the neuronal activity marker Fos with intact-brain mapping procedures to identify corresponding patterns of brain-wide activation. Relapse to food seeking was significantly higher after 60 abstinence days than after 1 or 15 days. Using unbiased ClearMap analysis, we identified increased activation of multiple brain regions, particularly corticostriatal structures, following 60 but not 1 or 15 abstinence days. We used orthogonal SMART2 analysis to confirm these findings within corticostriatal and thalamocortical subvolumes and applied expert-guided registration to investigate subdivision and layer-specific activation patterns. Overall, we 1) identified brain-wide activity patterns during incubation of food seeking using complementary analytical approaches and 2) provide a single-cell resolution whole-brain atlas that can be used to identify functional networks and global architecture underlying the incubation of food craving.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34675078,

title = {Orbitofrontal cortex and dorsal striatum functional connectivity predicts incubation of opioid craving after voluntary abstinence},

author = {Ida Fredriksson and Pei-Jung Tsai and Aniruddha Shekara and Ying Duan and Sarah V Applebey and Hanbing Lu and Jennifer M Bossert and Yavin Shaham and Yihong Yang},

url = {https://pubmed.ncbi.nlm.nih.gov/34675078/},

doi = {10.1073/pnas.2106624118},

issn = {1091-6490},

year  = {2021},

date = {2021-10-01},

urldate = {2021-10-01},

journal = {Proc Natl Acad Sci U S A},

volume = {118},

number = {43},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32305216,

title = {In a Rat Model of Opioid Maintenance, the G Protein-Biased Mu Opioid Receptor Agonist TRV130 Decreases Relapse to Oxycodone Seeking and Taking and Prevents Oxycodone-Induced Brain Hypoxia},

author = {Jennifer M Bossert and Eugene A Kiyatkin and Hannah Korah and Jennifer K Hoots and Anum Afzal and David Perekopskiy and Shruthi Thomas and Ida Fredriksson and Bruce E Blough and S Stevens Negus and David H Epstein and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/32305216/},

doi = {10.1016/j.biopsych.2020.02.014},

issn = {1873-2402},

year  = {2020},

date = {2020-02-24},

urldate = {2026-07-30},

journal = {Biol Psychiatry},

volume = {88},

number = {12},

pages = {935--944},

abstract = {BACKGROUND: Maintenance treatment with opioid agonists (buprenorphine, methadone) is effective for opioid addiction but does not eliminate opioid use in all patients. We modeled maintenance treatment in rats that self-administered the prescription opioid oxycodone. The maintenance medication was either buprenorphine or the G protein-biased mu opioid receptor agonist TRV130. We then tested prevention of oxycodone seeking and taking during abstinence using a modified context-induced reinstatement procedure, a rat relapse model.nnMETHODS: We trained rats to self-administer oxycodone (6 hours/day, 14 days) in context A; infusions were paired with discrete tone-light cues. We then implanted osmotic pumps containing buprenorphine or TRV130 (0, 3, 6, or 9 mg/kg/day) and performed 3 consecutive tests: lever pressing reinforced by oxycodone-associated discrete cues in nondrug context B (extinction responding), context-induced reinstatement of oxycodone seeking in context A, and reacquisition of oxycodone self-administration in context A. We also tested whether TRV130 maintenance would protect against acute oxycodone-induced decreases in nucleus accumbens oxygen levels.nnRESULTS: In male rats, buprenorphine and TRV130 decreased extinction responding and reacquisition of oxycodone self-administration but had a weaker (nonsignificant) effect on context-induced reinstatement. In female rats, buprenorphine decreased responding in all 3 tests, while TRV130 decreased only extinction responding. In both sexes, TRV130 prevented acute brain hypoxia induced by moderate doses of oxycodone.nnCONCLUSIONS: TRV130 decreased oxycodone seeking and taking during abstinence in a partly sex-specific manner and prevented acute oxycodone-induced brain hypoxia. We propose that G protein-biased mu opioid receptor agonists, currently in development as analgesics, should be considered as relapse prevention maintenance treatment for opioid addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Venniro:2020fk,

title = {Abstinence-dependent dissociable central amygdala microcircuits control drug craving.},

author = {Marco Venniro and Trinity I Russell and Leslie A Ramsey and Christopher T Richie and Heidi M B Lesscher and Simone M Giovanetti and Robert O Messing and Yavin Shaham},

url = {https://www.ncbi.nlm.nih.gov/pubmed/32205443},

doi = {10.1073/pnas.2001615117},

issn = {1091-6490 (Electronic); 0027-8424 (Linking)},

year  = {2019},

date = {2019-03-23},

urldate = {2019-03-23},

journal = {Proc Natl Acad Sci U S A},

address = {Behavioral Neuroscience Branch Intramural Research Program, National Institute on Drug Abuse (NIDA), NIH, Baltimore, MD 21224; venniro.marco@nih.gov yshaham@intra.nida.nih.gov.},

abstract = {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-Cdelta (PKCdelta)-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 PKCdelta and SOM in incubation using short-hairpin RNAs against PKCdelta or SOM that we developed and validated. We injected two groups with shPKCdelta or shCtrlPKCdelta 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 (shPKCdelta groups) or homecage forced abstinence (shSOM groups). After test day 15, we assessed PKCdelta and SOM, Fos, and double-labeled expression in CeL and central amygdala medial division (CeM). shPKCdelta CeL injections decreased Fos in CeL PKCdelta-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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Venniro:2018aab,

title = {Volitional social interaction prevents drug addiction in rat models.},

author = {Marco Venniro and Michelle Zhang and Daniele Caprioli and Jennifer K Hoots and Sam A Golden and Conor Heins and Marisela Morales and David H Epstein and Yavin Shaham},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30323276},

doi = {10.1038/s41593-018-0246-6},

issn = {1546-1726 (Electronic); 1097-6256 (Linking)},

year  = {2018},

date = {2018-11-01},

urldate = {2018-11-01},

journal = {Nat Neurosci},

volume = {21},

number = {11},

pages = {1520--1529},

address = {Intramural Research Program, NIDA, NIH, Baltimore, MD, USA. venniro.marco@nih.gov.},

abstract = {Addiction treatment has not been appreciably improved by neuroscientific research. One problem is that mechanistic studies using rodent models do not incorporate volitional social factors, which play a critical role in human addiction. Here, using rats, we introduce an operant model of choice between drugs and social interaction. Independent of sex, drug class, drug dose, training conditions, abstinence duration, social housing, or addiction score in Diagnostic & Statistical Manual IV-based and intermittent access models, operant social reward prevented drug self-administration. This protection was lessened by delay or punishment of the social reward but neither measure was correlated with the addiction score. Social-choice-induced abstinence also prevented incubation of methamphetamine craving. This protective effect was associated with activation of central amygdala PKCdelta-expressing inhibitory neurons and inhibition of anterior insular cortex activity. These findings highlight the need for incorporating social factors into neuroscience-based addiction research and support the wider implantation of socially based addiction treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40148031,

title = {Neurobiology of the incubation of drug craving: An update},

author = {Jonathan J Chow and Kayla M Pitts and Kenichiro Negishi and Rajtarun Madangopal and Yan Dong and Marina E Wolf and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/40148031/},

doi = {10.1016/j.pharmr.2024.100022},

issn = {1521-0081},

year  = {2025},

date = {2025-03-01},

urldate = {2025-03-01},

journal = {Pharmacol Rev},

volume = {77},

number = {2},

pages = {100022},

abstract = {Relapse to drug use is often preceded by drug craving. Clinical observations in the 1980s led clinical investigators to postulate that cue-induced cocaine craving may increase during abstinence. Over 2 decades ago, investigators identified an analogous phenomenon in rats of time-dependent increases in drug-seeking behavior during homecage abstinence and termed it incubation of cocaine craving. In 2011, we reviewed the first decade of studies on brain mechanisms of incubation of drug craving. In this review, we provide an update on incubation-related brain mechanisms from studies published since 2011. We first review studies using the standard method of incubation after homecage-forced abstinence from cocaine, methamphetamine, opioid drugs, and nicotine. Next, we review studies using newer methods to study incubation after voluntary abstinence in the drug environment. In these studies, abstinence is achieved by either providing rats alternative nondrug rewards in a choice setting or introducing rats to adverse consequences to drug seeking or taking. We then discuss translational human studies on incubation of cue-induced drug craving. We conclude by discussing several emerging topics, including sex differences in incubation of drug craving, role of sleep patterns, and similarities and differences in mechanisms of incubation of craving across drug classes and abstinence conditions. Our 2 main conclusions are as follows: (1) across drug classes, there are both similarities and differences in mechanisms of incubation of drug craving after forced abstinence, and (2) the method used to achieve abstinence (forced or voluntary) can influence the mechanisms controlling incubation of drug craving or its expression. SIGNIFICANCE STATEMENT: This article reviews results from preclinical and clinical studies published since 2011 on neurobiological mechanisms of incubation of drug craving after homecage-forced abstinence or voluntary abstinence in the drug environment. This article also reviews translational human studies on incubation of cue-induced subjective drug craving and brain response during abstinence. The results of the studies reviewed indicate that multiple brain mechanisms control incubation of drug craving after homecage-forced abstinence or voluntary abstinence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34987089,

title = {Sex Differences in Opioid and Psychostimulant Craving and Relapse: A Critical Review},

author = {Céline Nicolas and Natalie E Zlebnik and Mehdi Farokhnia and Lorenzo Leggio and Satoshi Ikemoto and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/34987089/},

doi = {10.1124/pharmrev.121.000367},

issn = {1521-0081},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Pharmacol Rev},

volume = {74},

number = {1},

pages = {119--140},

abstract = {A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinction of drug self-administration, and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones' role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women.The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because most of the studies reviewed were correlational, not sufficiently powered, and not a priori designed to detect sex differences. Additionally, imaging studies suggest sex differences in brain responses to cocaine cues and stress. The results of the preclinical studies reviewed provide evidence for sex differences in stress-induced reinstatement and incubation of cocaine craving but not cue- or cocaine-induced reinstatement of cocaine seeking. These sex differences are modulated in part by ovarian hormones. In contrast, the available data do not support the notion of sex differences in craving and relapse/reinstatement for methamphetamine or opioids in rodent models. SIGNIFICANCE STATEMENT: This systematic review summarizes clinical and preclinical studies on sex differences in psychostimulant and opioid craving and relapse. Results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. Results of preclinical studies reviewed provide evidence for sex differences in reinstatement and incubation of cocaine seeking but not for reinstatement or incubation of methamphetamine or opioid seeking.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Fredriksson1050,

title = {Animal Models of Drug Relapse and Craving after Voluntary Abstinence: A Review},

author = {Ida Fredriksson and Marco Venniro and David J Reiner and Jonathan J Chow and Jennifer M Bossert and Yavin Shaham},

editor = {Michael Nader},

url = {https://pubmed.ncbi.nlm.nih.gov/34257149/},

doi = {10.1124/pharmrev.120.000191},

issn = {0031-6997},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Pharmacological Reviews},

volume = {73},

number = {3},

pages = {1050--1083},

publisher = {American Society for Pharmacology and Experimental Therapeutics},

abstract = {Relapse to drug use during abstinence is a defining feature of addiction. During the last several decades, this clinical scenario has been studied at the preclinical level using classic relapse/reinstatement models in which drug seeking is assessed after experimenter-imposed home-cage forced abstinence or extinction of the drug-reinforced responding in the self-administration chambers. To date, however, results from studies using rat relapse/reinstatement models have yet to result in Food and Drug Administration–approved medications for relapse prevention. The reasons for this state of affairs are complex and multifaceted, but one potential reason is that, in humans, abstinence is often self-imposed or voluntary and occurs either because the negative consequences of drug use outweigh the drugtextquoterights rewarding effects or because of the availability of nondrug alternative rewards that are chosen over the drug. Based on these considerations, we and others have recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking (punishment) or seeking (electric barrier) or by providing mutually exclusive choices between the self-administered drug and nondrug rewards (palatable food or social interaction). In this review, we provide an overview of these translationally relevant relapse models and discuss recent neuropharmacological findings from studies using these models. We also discuss sex as a biological variable, future directions, and clinical implications of results from relapse studies using voluntary abstinence models. Our main conclusion is that the neuropharmacological mechanisms controlling relapse to drug seeking after voluntary abstinence are often different from the mechanisms controlling relapse after home-cage forced abstinence or reinstatement after extinction.Significance Statement This review describes recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking or seeking or by providing mutually exclusive choices between the self-administered drug and nondrug rewards. This review discusses recent neuropharmacological findings from studies using these models and discusses future directions and clinical implications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Venniro:2020aa,

title = {Improving translation of animal models of addiction and relapse by reverse translation},

author = {Marco Venniro and Matthew L Banks and Markus Heilig and David H Epstein and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/33024318/},

doi = {10.1038/s41583-020-0378-z},

isbn = {1471-0048},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Nature Reviews Neuroscience},

abstract = {Critical features of human addiction are increasingly being incorporated into complementary animal models, including escalation of drug intake, punished drug seeking and taking, intermittent drug access, choice between drug and non-drug rewards, and assessment of individual differences based on criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Combined with new technologies, these models advanced our understanding of brain mechanisms of drug self-administration and relapse, but these mechanistic gains have not led to improvements in addiction treatment. This problem is not unique to addiction neuroscience, but it is an increasing source of disappointment and calls to regroup. Here we first summarize behavioural and neurobiological results from the animal models mentioned above. We then propose a reverse translational approach, whose goal is to develop models that mimic successful treatments: opioid agonist maintenance, contingency management and the community-reinforcement approach. These reverse-translated `treatments'may provide an ecologically relevant platform from which to discover new circuits, test new medications and improve translation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38123817,

title = {Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model},

author = {Shinbe Choi and Matthew R Irwin and Michael R Noya and Yavin Shaham and Eugene A Kiyatkin},

url = {https://pubmed.ncbi.nlm.nih.gov/38123817/},

doi = {10.1038/s41386-023-01782-2},

issn = {1740-634X},

year  = {2023},

date = {2023-12-01},

urldate = {2023-12-01},

journal = {Neuropsychopharmacology},

abstract = {Xylazine, a veterinary tranquillizer known by drug users as "Tranq", is being increasingly detected in people who overdose on opioid drugs, indicating enhanced health risk of fentanyl-xylazine mixtures. We recently found that xylazine potentiates fentanyl- and heroin-induced brain hypoxia and eliminates the rebound-like post-hypoxic oxygen increases. Here, we used oxygen sensors coupled with high-speed amperometry in rats of both sexes to explore the treatment potential of naloxone plus atipamezole, a selective α2-adrenoceptor antagonist, in reversing brain (nucleus accumbens) and periphery (subcutaneous space) hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with naloxone (0.2 mg/kg, IV) fully blocked brain and peripheral hypoxia induced by fentanyl (20 μg/kg, IV), but only partially decreased hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with atipamezole (0.25 mg/kg, IV) fully blocked the hypoxic effects of xylazine (1.0 mg/kg, IV), but not fentanyl. Pretreatment with atipamezole + naloxone was more potent than naloxone alone in blocking the hypoxic effects of the fentanyl-xylazine mixture. Both naloxone and naloxone + atipamezole, delivered at the peak of brain hypoxia (3 min post fentanyl-xylazine exposure), reversed the rapid initial brain hypoxia, but only naloxone + atipamezole decreased the prolonged weaker hypoxia. There were no sex differences in the effects of the different drugs and their combinations on brain and peripheral oxygen responses. Results indicate that combined treatment with naloxone and atipamezole is more effective than naloxone alone in reversing the hypoxic effects of fentanyl-xylazine mixtures. Naloxone + atipamezole treatment should be considered in preventing overdoses induced by fentanyl-xylazine mixtures in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36940812,

title = {The pattern of brain oxygen response induced by intravenous fentanyl limits the time window of therapeutic efficacy of naloxone},

author = {Carlos M Curay and Matthew R Irwin and Eugene A Kiyatkin},

url = {https://pubmed.ncbi.nlm.nih.gov/36940812/},

doi = {10.1016/j.neuropharm.2023.109507},

issn = {1873-7064},

year  = {2023},

date = {2023-06-01},

urldate = {2023-06-01},

journal = {Neuropharmacology},

volume = {231},

pages = {109507},

abstract = {Opioids induce respiratory depression resulting in coma or even death during overdose. Naloxone, an opioid antagonist, is the gold standard reversal agent for opioid intoxication, but this treatment is often less successful for fentanyl. While low dosing is thought to be a factor limiting naloxone's efficacy, the timing between fentanyl exposure and initiation of naloxone treatment may be another important factor. Here, we used oxygen sensors coupled with amperometry to examine the pattern of oxygen responses in the brain and periphery induced by intravenous fentanyl in freely moving rats. At both doses (20 and 60 μg/kg), fentanyl induced a biphasic brain oxygen response-a rapid, strong, and relatively transient decrease (8-12 min) followed by a weaker and prolonged increase. In contrast, fentanyl induced stronger and more prolonged monophasic oxygen decreases in the periphery. When administered before fentanyl, intravenous naloxone (0.2 mg/kg) fully blocked the hypoxic effects of moderate-dose fentanyl in both the brain and periphery. However, when injected 10 min after fentanyl, when most of hypoxia had already ceased, naloxone had minimal effect on central and peripheral oxygen levels, but at a higher dose, it strongly attenuated hypoxic effects in the periphery with only a transient brain oxygen increase associated with behavioral awakening. Therefore, due to the rapid, strong but transient nature of fentanyl-induced brain hypoxia, the time window when naloxone can attenuate this effect is relatively short. This timing limitation is critical, making naloxone most effective when used quickly and less effective when used during the post-hypoxic comatose state after brain hypoxia has already ceased and harm for neural cells already done.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}