Selected recent publications and reviews
Shaham group
Selected recent empirical papers
Venniro, Marco; Zhang, Michelle; Caprioli, Daniele; Hoots, Jennifer K; Golden, Sam A; Heins, Conor; Morales, Marisela; Epstein, David H; Shaham, Yavin Volitional social interaction prevents drug addiction in rat models. Journal Article In: Nat Neurosci, vol. 21, no. 11, pp. 1520–1529, 2018, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking). @article{Venniro:2018aab,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. |
Venniro, Marco; Russell, Trinity I; Ramsey, Leslie A; Richie, Christopher T; Lesscher, Heidi M B; Giovanetti, Simone M; Messing, Robert O; Shaham, Yavin Abstinence-dependent dissociable central amygdala microcircuits control drug craving. Journal Article In: Proc Natl Acad Sci U S A, 2019, ISSN: 1091-6490 (Electronic); 0027-8424 (Linking). @article{Venniro:2020fk,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. |
Golden, Sam A; Jin, Michelle; Heins, Conor; Venniro, Marco; Michaelides, Michael; Shaham, Yavin Nucleus Accumbens Drd1-Expressing Neurons Control Aggression Self-Administration and Aggression Seeking in Mice Journal Article In: J Neurosci, vol. 39, no. 13, pp. 2482–2496, 2019, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking). @article{Golden2019,We recently developed a mouse model of appetitive operant aggression and reported that adult male outbred CD-1 mice lever-press for the opportunity to attack subordinate male mice and relapse to aggression seeking during abstinence. Here we studied the role of nucleus accumbens (NAc) dopamine receptor (Drd)1- and Drd2-expressing neurons in aggression self-administration and aggression seeking. We trained CD-1 mice to self-administer intruders (9 d, 12 trials/d) and tested them for aggression self-administration and aggression seeking on abstinence Day 1. We used immunohistochemistry and in situ hybridization to measure the neuronal activity marker Fos in the NAc, and cell-type-specific colocalization of Fos with Drd1- and Drd2-expressing neurons. To test the causal role of Drd1- and Drd2-expressing neurons, we validated a transgenic hybrid breeding strategy crossing inbred Drd1-Cre and Drd2-Cre transgenic mice with outbred CD-1 mice and used cell-type-specific Cre-DREADD (hM4Di) to inhibit NAc Drd1- and Drd2-expressing neuron activity. We found that aggression self-administration and aggression seeking induced higher Fos expression in NAc shell than in core, that Fos colocalized with Drd1 and Drd2 in both subregions, and that chemogenetic inhibition of Drd1-, but not Drd2-, expressing neurons decreased aggression self-administration and aggression seeking. Results indicate a cell-type-specific role of Drd1-expressing neurons that is critical for both aggression self-administration and aggression seeking. Our study also validates a simple breeding strategy between outbred CD-1 mice and inbred C57-based Cre lines that can be used to study cell-type and circuit mechanisms of aggression reward and relapse. SIGNIFICANCE STATEMENT Aggression is often comorbid with neuropsychiatric diseases, including drug addiction. One form, appetitive aggression, exhibits symptomatology that mimics that of drug addiction and is hypothesized to be due to dysregulation of addiction-related reward circuits. However, our mechanistic understanding of the circuitry modulating appetitive operant aggression is limited. Here we used a novel mouse model of aggression self-administration and relapse, in combination with immunohistochemistry, in situ hybridization, and chemogenetic manipulations to examine how cell types in the nucleus accumbens are recruited for, and control, operant aggression self-administration and aggression seeking on abstinence Day 1. We found that one population, dopamine receptor 1-expressing neurons, act as a critical modulator of operant aggression reward and aggression seeking. |
Bossert, Jennifer M; Kiyatkin, Eugene A; Korah, Hannah; Hoots, Jennifer K; Afzal, Anum; Perekopskiy, David; Thomas, Shruthi; Fredriksson, Ida; Blough, Bruce E; Negus, Stevens S; Epstein, David H; Shaham, Yavin In: Biological Psychiatry, vol. 88, no. 12, pp. 935–944, 2020, ISBN: 0006-3223. @article{Bossert:2020aa,BackgroundMaintenance 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. |
Fredriksson, Ida; Tsai, Pei-Jung; Shekara, Aniruddha; Duan, Ying; Applebey, Sarah V; Lu, Hanbing; Bossert, Jennifer M; Shaham, Yavin; Yang, Yihong Orbitofrontal cortex and dorsal striatum functional connectivity predicts incubation of opioid craving after voluntary abstinence Journal Article In: Proc Natl Acad Sci U S A, vol. 118, no. 43, 2021, ISSN: 1091-6490. @article{pmid34675078,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. |
Ramsey, Leslie A; Holloman, Fernanda M; Hope, Bruce T; Shaham, Yavin; Venniro, Marco Waving Through the Window: A Model of Volitional Social Interaction in Female Mice Journal Article In: Biol Psychiatry, vol. 91, no. 11, pp. 988–997, 2022, ISSN: 1873-2402. @article{pmid35074211,BACKGROUND: Mouse models of social behavior fail to account for volitional aspects of social interaction, and current neurobiological investigation of social behavior is performed almost exclusively using C57BL/6J mice, the background strain of most transgenic mice. Here, we introduce a mouse model of operant social self-administration and choice, using a custom-made apparatus.nnMETHODS: First, we trained adolescent and adult female C57BL/6J and CD1 mice to self-administer palatable food pellets and then to lever press under increasing fixed-ratio response requirements for access to an age-matched female social partner. Next, we tested their motivation to seek social interaction using a progressive ratio reinforcement schedule, relapse to social seeking after social isolation, and choice between palatable food versus social interaction. We also tested social conditioned place preference in adult female CD1 and C57BL/6J mice.nnRESULTS: Adolescent and adult female mice of both strains showed similar rates of food self-administration. In contrast, CD1 mice demonstrated significantly stronger social self-administration than C57BL/6J mice under both reinforcement schedules. CD1 but not C57BL/6J mice demonstrated robust social seeking after social isolation. In the choice task, CD1 mice preferred social interaction, whereas C57BL/6J mice preferred food. CD1 but not C57BL/6J mice demonstrated robust social conditioned place preference. The strain differences were age independent.nnCONCLUSIONS: Our data show that CD1 mice are a better strain for studying female social reward learning. Our mouse operant social model provides a tool for research on neurobiological substrates of female social reward and disruption of social reward in psychiatric disorders using mouse-specific genetic tools. |
Fredriksson, Ida; Tsai, Pei-Jung; Shekara, Aniruddha; Duan, Ying; Applebey, Sarah V; Minier-Toribio, Angelica; Batista, Ashley; Chow, Jonathan J; Altidor, Lindsay; Barbier, Estelle; Cifani, Carlo; Li, Xuan; Reiner, David J; Rubio, F Javier; Hope, Bruce T; Yang, Yihong; Bossert, Jennifer M; Shaham, Yavin Role of ventral subiculum neuronal ensembles in incubation of oxycodone craving after electric barrier-induced voluntary abstinence Journal Article In: Sci Adv, vol. 9, no. 2, pp. eadd8687, 2023, ISSN: 2375-2548. @article{pmid36630511,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. |
Bossert, Jennifer M; Mejias-Aponte, Carlos A; Saunders, Thomas; Altidor, Lindsay; Emery, Michael; Fredriksson, Ida; Batista, Ashley; Claypool, Sarah M; Caldwell, Kiera E; Reiner, David J; Chow, Jonathan J; Foltz, Matthew; Kumar, Vivek; Seasholtz, Audrey; Hughes, Elizabeth; Filipiak, Wanda; Harvey, Brandon K; Richie, Christopher T; Vautier, Francois; Gomez, Juan L; Michaelides, Michael; Kieffer, Brigitte L; Watson, Stanley J; Akil, Huda; Shaham, Yavin In: J Neurosci, vol. 43, no. 10, pp. 1692–1713, 2023, ISSN: 1529-2401. @article{pmid36717230,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. |
Claypool, Sarah M; Reiner, David J; Behdin, Sana; Orihuel, Javier; Batista, Ashley; Caldwell, Kiera E; Chow, Jonathan J; Bossert, Jennifer M; Rubio, F Javier; Hope, Bruce T; Shaham, Yavin Role of Piriform Cortex and Its Afferent Projections in Relapse to Fentanyl Seeking after Food Choice-Induced Voluntary Abstinence Journal Article In: J Neurosci, vol. 43, no. 14, pp. 2597–2614, 2023, ISSN: 1529-2401. @article{pmid36898838,We previously demonstrated a role of piriform cortex (Pir) in relapse to fentanyl seeking after food choice-induced voluntary abstinence. Here, we used this model to further study the role of Pir and its afferent projections in fentanyl relapse. We trained male and female rats to self-administer palatable food pellets for 6 d (6 h/day) and fentanyl (2.5 µg/kg/infusion, i.v.) for 12 d (6 h/day). We assessed relapse to fentanyl seeking after 12 voluntary abstinence sessions, achieved through a discrete choice procedure between fentanyl and palatable food (20 trials/session). We determined projection-specific activation of Pir afferents during fentanyl relapse with Fos plus the retrograde tracer cholera toxin B (injected into Pir). Fentanyl relapse was associated with increased Fos expression in anterior insular cortex (AI) and prelimbic cortex (PL) neurons projecting to Pir. We next used an anatomical disconnection procedure to determine the causal role of these two projections (AI→Pir and PL→Pir) in fentanyl relapse. Contralateral but not ipsilateral disconnection of AI→Pir projections decreased fentanyl relapse but not reacquisition of fentanyl self-administration. In contrast, contralateral but not ipsilateral disconnection of PL→Pir projections modestly decreased reacquisition but not relapse. Fluorescence-activated cell sorting and quantitative PCR data showed molecular changes within Pir Fos-expressing neurons associated with fentanyl relapse. Finally, we found minimal or no sex differences in fentanyl self-administration, fentanyl versus food choice, and fentanyl relapse. Our results indicate that AI→Pir and PL→Pir projections play dissociable roles in nonreinforced relapse to fentanyl seeking versus reacquisition of fentanyl self-administration after food choice-induced voluntary abstinence. We previously showed a role of Pir in fentanyl relapse after food choice-induced voluntary abstinence in rats, a procedure mimicking human abstinence or a significant reduction in drug self-administration because of the availability of alternative nondrug rewards. Here, we aimed to further characterize the role of Pir in fentanyl relapse by investigating the role of Pir afferent projections and analyzing molecular changes in relapse-activated Pir neurons. We identified dissociable roles of two Pir afferent projections (AI→Pir and PL→Pir) in relapse to fentanyl seeking versus reacquisition of fentanyl self-administration after voluntary abstinence. We also characterized molecular changes within Pir Fos-expressing neurons associated with fentanyl relapse. |
Claypool, Sarah M; Reiner, David J; Behdin, Sana; Orihuel, Javier; Batista, Ashley; Caldwell, Kiera E; Chow, Jonathan J; Bossert, Jennifer M; Rubio, F Javier; Hope, Bruce T; Shaham, Yavin Role of Piriform Cortex and Its Afferent Projections in Relapse to Fentanyl Seeking after Food Choice-Induced Voluntary Abstinence Journal Article In: J Neurosci, vol. 43, no. 14, pp. 2597–2614, 2023, ISSN: 1529-2401. @article{pmid36898838b,We previously demonstrated a role of piriform cortex (Pir) in relapse to fentanyl seeking after food choice-induced voluntary abstinence. Here, we used this model to further study the role of Pir and its afferent projections in fentanyl relapse. We trained male and female rats to self-administer palatable food pellets for 6 d (6 h/day) and fentanyl (2.5 µg/kg/infusion, i.v.) for 12 d (6 h/day). We assessed relapse to fentanyl seeking after 12 voluntary abstinence sessions, achieved through a discrete choice procedure between fentanyl and palatable food (20 trials/session). We determined projection-specific activation of Pir afferents during fentanyl relapse with Fos plus the retrograde tracer cholera toxin B (injected into Pir). Fentanyl relapse was associated with increased Fos expression in anterior insular cortex (AI) and prelimbic cortex (PL) neurons projecting to Pir. We next used an anatomical disconnection procedure to determine the causal role of these two projections (AI→Pir and PL→Pir) in fentanyl relapse. Contralateral but not ipsilateral disconnection of AI→Pir projections decreased fentanyl relapse but not reacquisition of fentanyl self-administration. In contrast, contralateral but not ipsilateral disconnection of PL→Pir projections modestly decreased reacquisition but not relapse. Fluorescence-activated cell sorting and quantitative PCR data showed molecular changes within Pir Fos-expressing neurons associated with fentanyl relapse. Finally, we found minimal or no sex differences in fentanyl self-administration, fentanyl versus food choice, and fentanyl relapse. Our results indicate that AI→Pir and PL→Pir projections play dissociable roles in nonreinforced relapse to fentanyl seeking versus reacquisition of fentanyl self-administration after food choice-induced voluntary abstinence. We previously showed a role of Pir in fentanyl relapse after food choice-induced voluntary abstinence in rats, a procedure mimicking human abstinence or a significant reduction in drug self-administration because of the availability of alternative nondrug rewards. Here, we aimed to further characterize the role of Pir in fentanyl relapse by investigating the role of Pir afferent projections and analyzing molecular changes in relapse-activated Pir neurons. We identified dissociable roles of two Pir afferent projections (AI→Pir and PL→Pir) in relapse to fentanyl seeking versus reacquisition of fentanyl self-administration after voluntary abstinence. We also characterized molecular changes within Pir Fos-expressing neurons associated with fentanyl relapse. |
Choi, Shinbe; Irwin, Matthew R; Noya, Michael R; Shaham, Yavin; Kiyatkin, Eugene A In: Neuropsychopharmacology, 2023, ISSN: 1740-634X. @article{pmid38123817,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. |
Chow, Jonathan J; Pitts, Kayla M; Schoenbaum, Ansel; Costa, Kauê M; Schoenbaum, Geoffrey; Shaham, Yavin Different Effects of Peer Sex on Operant Responding for Social Interaction and Striatal Dopamine Activity Journal Article In: J Neurosci, vol. 44, no. 10, 2024, ISSN: 1529-2401. @article{pmid38346894,When rats are given discrete choices between social interactions with a peer and opioid or psychostimulant drugs, they choose social interaction, even after extensive drug self-administration experience. Studies show that like drug and nondrug food reinforcers, social interaction is an operant reinforcer and induces dopamine release. However, these studies were conducted with same-sex peers. We examined if peer sex influences operant social interaction and the role of estrous cycle and striatal dopamine in same- versus opposite-sex social interaction. We trained male and female rats ( = 13 responders/12 peers) to lever-press (fixed-ratio 1 [FR1] schedule) for 15 s access to a same- or opposite-sex peer for 16 d (8 d/sex) while tracking females' estrous cycle. Next, we transfected GRAB-DA2m and implanted optic fibers into nucleus accumbens (NAc) core and dorsomedial striatum (DMS). We then retrained the rats for 15 s social interaction (FR1 schedule) for 16 d (8 d/sex) and recorded striatal dopamine during operant responding for a peer for 8 d (4 d/sex). Finally, we assessed economic demand by manipulating FR requirements for a peer (10 d/sex). In male, but not female rats, operant responding was higher for the opposite-sex peer. Female's estrous cycle fluctuations had no effect on operant social interaction. Striatal dopamine signals for operant social interaction were dependent on the peer's sex and striatal region (NAc core vs DMS). Results indicate that estrous cycle fluctuations did not influence operant social interaction and that NAc core and DMS dopamine activity reflect sex-dependent features of volitional social interaction. |
Selected recent reviews
Venniro, Marco; Banks, Matthew L; Heilig, Markus; Epstein, David H; Shaham, Yavin Improving translation of animal models of addiction and relapse by reverse translation Journal Article In: Nature Reviews Neuroscience, 2020, ISBN: 1471-0048. @article{Venniro:2020aa,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. |
Fredriksson, Ida; Venniro, Marco; Reiner, David J; Chow, Jonathan J; Bossert, Jennifer M; Shaham, Yavin Animal Models of Drug Relapse and Craving after Voluntary Abstinence: A Review Journal Article In: Pharmacological Reviews, vol. 73, no. 3, pp. 1050–1083, 2021, ISSN: 0031-6997. @article{Fredriksson1050,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. |
Nicolas, Céline; Zlebnik, Natalie E; Farokhnia, Mehdi; Leggio, Lorenzo; Ikemoto, Satoshi; Shaham, Yavin Sex Differences in Opioid and Psychostimulant Craving and Relapse: A Critical Review Journal Article In: Pharmacol Rev, vol. 74, no. 1, pp. 119–140, 2022, ISSN: 1521-0081. @article{pmid34987089,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. |
Negishi, Kenichiro; Fredriksson, Ida; Bossert, Jennifer M; Zangen, Abraham; Shaham, Yavin Relapse after electric barrier-induced voluntary abstinence: A review Journal Article In: Curr Opin Neurobiol, vol. 86, pp. 102856, 2024, ISSN: 1873-6882. @article{pmid38508102,Relapse to drug use during abstinence is a defining feature of addiction. To date, however, results from studies using rat relapse/reinstatement models have yet to result in FDA-approved medications for relapse prevention. To address this translational gap, we and others have developed rat models of relapse after voluntary abstinence from drug self-administration. One of these models is the electric barrier conflict model. Here, we introduce the model, and then review studies on behavioral and neuropharmacological mechanisms of cue-induced relapse and incubation of drug seeking (time-dependent increase in drug seeking during abstinence) after electric barrier-induced abstinence. We also briefly discuss future directions and potential clinical implications. One major conclusion of our review is that the brain mechanisms controlling drug relapse after electrical barrier-induced voluntary abstinence are likely distinct from those controlling relapse after homecage forced abstinence. |
Kiyatkin group
Irwin, Matthew R; Curay, Carlos M; Choi, Shinbe; Kiyatkin, Eugene A Basic metabolic and vascular effects of ketamine and its interaction with fentanyl Journal Article In: Neuropharmacology, vol. 228, pp. 109465, 2023, ISSN: 1873-7064. @article{pmid36801400,Ketamine is a short-acting general anesthetic with hallucinogenic, analgesic, and amnestic properties. In addition to its anesthetic use, ketamine is commonly abused in rave settings. While safe when used by medical professionals, uncontrolled recreational use of ketamine is dangerous, especially when mixed with other sedative drugs, including alcohol, benzodiazepines, and opioid drugs. Since synergistic antinociceptive interactions between opioids and ketamine were demonstrated in both preclinical and clinical studies, such an interaction could exist for the hypoxic effects of opioid drugs. Here, we focused on the basic physiological effects of ketamine as a recreational drug and its possible interactions with fentanyl-a highly potent opioid that induces strong respiratory depression and robust brain hypoxia. By using multi-site thermorecording in freely-moving rats, we showed that intravenous ketamine at a range of human relevant doses (3, 9, 27 mg/kg) dose-dependently increases locomotor activity and brain temperature, as assessed in the nucleus accumbens (NAc). By determining temperature differentials between the brain, temporal muscle, and skin, we showed that the brain hyperthermic effect of ketamine results from increased intracerebral heat production, an index of metabolic neural activation, and decreased heat loss due to peripheral vasoconstriction. By using oxygen sensors coupled with high-speed amperometry we showed that ketamine at the same doses increases NAc oxygen levels. Finally, co-administration of ketamine with intravenous fentanyl results in modest enhancement of fentanyl-induced brain hypoxia also enhancing the post-hypoxic oxygen increase. Therefore, in contrast to fentanyl, ketamine increases brain oxygenation but potentiates brain hypoxia induced by fentanyl. |
Curay, Carlos M; Irwin, Matthew R; Kiyatkin, Eugene A The pattern of brain oxygen response induced by intravenous fentanyl limits the time window of therapeutic efficacy of naloxone Journal Article In: Neuropharmacology, vol. 231, pp. 109507, 2023, ISSN: 1873-7064. @article{pmid36940812,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. |
Choi, Shinbe; Irwin, Matthew R; Noya, Michael R; Shaham, Yavin; Kiyatkin, Eugene A In: Neuropsychopharmacology, 2023, ISSN: 1740-634X. @article{pmid38123817,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. |
