The Experts below are selected from a list of 14049 Experts worldwide ranked by ideXlab platform
Yavin Shaham - One of the best experts on this subject based on the ideXlab platform.
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Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress
Neuropsychopharmacology, 2016Co-Authors: John R. Mantsch, David A. Baker, Douglas Funk, Anh D Lê, Yavin ShahamAbstract:In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced Reinstatement of drug seeking. Here, we first discuss the generality of stress-induced Reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced Reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced Reinstatement. Our main conclusions are (1) The phenomenon of stress-induced Reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce Reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced Reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse.
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role of corticostriatal circuits in context induced Reinstatement of drug seeking
Brain Research, 2015Co-Authors: Nathan J Marchant, Yavin Shaham, Konstantin Kaganovsky, Jennifer M BossertAbstract:Drug addiction is characterized by persistent relapse vulnerability during abstinence. In abstinent drug users, relapse is often precipitated by re-exposure to environmental contexts that were previously associated with drug use. This clinical scenario is modeled in preclinical studies using the context-induced Reinstatement procedure, which is based on the ABA renewal procedure. In these studies, context-induced Reinstatement of drug seeking is reliably observed in laboratory animals that were trained to self-administer drugs abused by humans. In this review, we summarize neurobiological findings from preclinical studies that have focused on the role of corticostriatal circuits in context-induced Reinstatement of heroin, cocaine, and alcohol seeking. We also discuss neurobiological similarities and differences in the corticostriatal mechanisms of context-induced Reinstatement across these drug classes. We conclude by briefly discussing future directions in the study of context-induced relapse to drug seeking in rat models. Our main conclusion from the studies reviewed is that there are both similarities (accumbens shell, ventral hippocampus, and basolateral amygdala) and differences (medial prefrontal cortex and its projections to accumbens) in the neural mechanisms of context-induced Reinstatement of cocaine, heroin, and alcohol seeking.
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the Reinstatement model of drug relapse recent neurobiological findings emerging research topics and translational research
Psychopharmacology, 2013Co-Authors: Jennifer M Bossert, Nathan J Marchant, Donna J Calu, Yavin ShahamAbstract:Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the Reinstatement model. In this model, Reinstatement of drug seeking by drug priming, drug cues or contexts, or certain stressors is assessed following drug self-administration training and subsequent extinction of the drug-reinforced responding. In this review, we first summarize recent (2009–present) neurobiological findings from studies using the Reinstatement model. We then discuss emerging research topics, including the impact of interfering with putative reconsolidation processes on cue- and context-induced Reinstatement of drug seeking, and similarities and differences in mechanisms of Reinstatement across drug classes. We conclude by discussing results from recent human studies that were inspired by results from rat studies using the Reinstatement model. Main conclusions from the studies reviewed highlight: (1) the ventral subiculum and lateral hypothalamus as emerging brain areas important for Reinstatement of drug seeking, (2) the existence of differences in brain mechanisms controlling Reinstatement of drug seeking across drug classes, (3) the utility of the Reinstatement model for assessing the effect of reconsolidation-related manipulations on cue-induced drug seeking, and (4) the encouraging pharmacological concordance between results from rat studies using the Reinstatement model and human laboratory studies on cue- and stress-induced drug craving.
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role of dorsal medial prefrontal cortex dopamine d1 family receptors in relapse to high fat food seeking induced by the anxiogenic drug yohimbine
Neuropsychopharmacology, 2011Co-Authors: Sunila G. Nair, Jennifer M Bossert, Charles L. Pickens, Brittany M Navarre, Carlo Cifani, Yavin ShahamAbstract:In humans, relapse to maladaptive eating habits during dieting is often provoked by stress. In rats, the anxiogenic drug yohimbine, which causes stress-like responses in both humans and nonhumans, reinstates food seeking in a relapse model. In this study, we examined the role of medial prefrontal cortex (mPFC) dopamine D1-family receptors, previously implicated in stress-induced Reinstatement of drug seeking, in yohimbine-induced Reinstatement of food seeking. We trained food-restricted rats to lever press for 35% high-fat pellets every other day (9–15 sessions, 3 h each); pellet delivery was accompanied by a discrete tone-light cue. We then extinguished operant responding for 10–16 days by removing the pellets. Subsequently, we examined the effect of yohimbine (2 mg/kg, i.p.) on Reinstatement of food seeking and Fos (a neuronal activity marker) induction in mPFC. We then examined the effect of systemic injections of the D1-family receptor antagonist SCH23390 (10 μg/kg, s.c.) on yohimbine-induced Reinstatement and Fos induction, and that of mPFC SCH23390 (0.5 and 1.0 μg/side) injections on this Reinstatement. Yohimbine-induced Reinstatement was associated with strong Fos induction in the dorsal mPFC and with weaker Fos induction in the ventral mPFC. Systemic SCH23390 injections blocked both yohimbine-induced Reinstatement and mPFC Fos induction. Dorsal, but not ventral, mPFC injections of SCH23390 decreased yohimbine-induced Reinstatement of food seeking. In addition, dorsal mPFC SCH23390 injections decreased pellet-priming-induced Reinstatement, but had no effect on ongoing high-fat pellet self-administration or discrete-cue-induced Reinstatement. Results indicate a critical role of dorsal mPFC dopamine D1-family receptors in stress-induced relapse to palatable food seeking, as well as relapse induced by acute re-exposure to food taste, texture, and smell.
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peptide yy3 36 decreases Reinstatement of high fat food seeking during dieting in a rat relapse model
The Journal of Neuroscience, 2007Co-Authors: Udi E Ghitza, Jennifer M Bossert, Sunila G. Nair, Sam A Golden, Sarah M Gray, Jamie L Uejima, Yavin ShahamAbstract:A major problem in treating obesity is high rates of relapse to maladaptive food-taking habits during dieting. This relapse is often provoked by acute re-exposure to palatable food, food-associated cues, or stress. We used a Reinstatement model, commonly used to study relapse to abused drugs, to explore the effect of peptide YY3-36 (PYY3-36) on Reinstatement of high-fat (35%, 45 mg pellets) food seeking induced by acute exposure to the pellets (pellet priming), a cue previously associated with pellet delivery (pellet cue), or yohimbine (2 mg/kg, a pharmacological stressor). Rats were placed on a restricted diet (16 g of chow per day) and lever-pressed for the pellets for 9-12 sessions (6 h/d, every 48 h); pellet delivery was paired with a tone-light cue. They were then given 10-20 extinction sessions wherein lever presses were not reinforced with the pellets and subsequently tested for Reinstatement of food seeking. Systemic PYY3-36 injections (100-200 microg/kg) decreased pellet priming- and pellet cue-induced Reinstatement of food seeking but not yohimbine-induced Reinstatement. Arcuate nucleus (Arc) injections of PYY3-36 (0.4 microg per side) decreased pellet priming-induced Reinstatement. The attenuation of pellet priming-induced Reinstatement by systemic PYY3-36 was reversed by systemic (2 mg/kg) but not Arc (0.5 microg per side) injections of the Y2 receptor antagonist BIIE0246. Arc PYY3-36 injections did not decrease pellet cue-induced Reinstatement. Finally, systemic PYY3-36 injections had minimal effects on ongoing food self-administration or heroin priming- or heroin cue-induced Reinstatement of heroin seeking. These data identify an effect of systemic PYY3-36 on relapse to food seeking that is independent of Y2 receptor activation in Arc and suggest that PYY3-36 should be considered for the treatment of relapse to maladaptive food-taking habits during dieting.
Peter W Kalivas - One of the best experts on this subject based on the ideXlab platform.
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Neurotensin in the ventral pallidum increases extracellular gamma-aminobutyric acid and differentially affects cue- and cocaine-primed
2020Co-Authors: Mary M Torregrossa, Peter W KalivasAbstract:ABSTRACT Cocaine-primed Reinstatement is an animal model of drug relapse. The neurocircuitry underlying cocaine-primed Reinstatement includes a decrease in GABA in the ventral pallidum (VP) that is inhibited by a opioid receptor antagonist, suggesting that opioid peptides colocalized with GABA in the projection from the nucleus accumbens to the VP may mediate this effect. Neurotensin is also colocalized with GABA and has been shown to increase GABA release in several brain regions. Therefore, the present study determined whether neurotensin increases GABA release in the VP, antagonizes cocaine-induced decreases in GABA, and prevents Reinstatement of cocaine seeking. In vivo microdialysis revealed that the neurotensin agonist neurotensin peptide fragment 8 -13 [NT(8 -13)] increased GABA in the VP in a neurotensin receptor and tetrodotoxin-dependent manner and blocked the cocaine-induced decrease in GABA. NT(8 -13) (3 nmol) microinjected into the VP prevented cue-induced Reinstatement without affecting cocaine self-administration. In contrast, 3 nmol NT(8 -13) potentiated cocaine-primed Reinstatement. The 3.1.13,7]decane-2-carboxylic acid) had no effect on any behavioral measure when infused in the VP at the dose tested but attenuated cocaine-primed Reinstatement when administered systemically. In contrast to Reinstatement, NT(8 -13) did not alter the motor response to acute cocaine or the development of motor sensitization by chronic cocaine. Three conclusions can be drawn from these data: 1) neurotensin promotes GABA release in the VP and correspondingly inhibits cue-induced Reinstatement, 2) neurotensin and cocaine interact in a manner that countermands the neurotensin-induced increase in GABA and promotes Reinstatement, and 3) endogenous release of neurotensin in the VP is not necessary for Reinstatement. Drug addiction is a serious public health issue, and one of the most problematic aspects of addiction is the tendency to relapse even after extended periods of abstinence. Relapse can be studied in rodents using a combination of neurochemical and behavioral methods, including Reinstatement of drug seeking. In this model, animals are trained to self-administer a drug of abuse, this behavior is then extinguished by removal of the reinforcer, and then drug seeking is reinstated by exposure to a stressor, drug-associated cue, or the drug itself (Shalev et a
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glutamate transporter glt 1 mediates n acetylcysteine inhibition of cocaine Reinstatement
Addiction Biology, 2015Co-Authors: Lori A Knackstedt, Kathryn J Reissner, Cassandra D Gipson, Phuong K Tran, Michael D Scofield, Peter W KalivasAbstract:Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced Reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/Reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced Reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit Reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting Reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased Reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented Reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine Reinstatement.
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The Circuitry Mediating Cocaine-Induced Reinstatement of Drug- Seeking Behavior
2013Co-Authors: Krista Mcfarl, Peter W KalivasAbstract:The role of limbic-striato-pallidal circuitry in cocaine-induced Reinstatement was evaluated. The transient inhibition of brain nuclei associated with motor systems [including the ventral tegmental area (VTA), dorsal prefrontal cortex (dPFC), core of the nucleus accumbens (NAcore), and ventral pallidum (VP)] prevented cocaine-induced Reinstatement. However, only the VP proved to be necessary for food Reinstatement, suggesting that the identified circuit is specific to drug-related Reinstatement. Supporting the possibility that the VTA–dPFC–NAcore–VP is a series circuit mediating Reinstatement, simultaneous unilateral microinjection of GABA agonists into the dPFC in one hemisphere and into the VP in the contralateral hemisphere abolished cocaine Reinstatement. Although dopamine projections from the VTA innervate all three forebrain nuclei, the blockade of dopamine receptors only in the dPFC antagonized cocaine-induced Reinstatement. Furthermore, DA administration into the dPFC was sufficient to elicit a Reinstatement in drug-related responding. These data demonstrate that dopamine release in the dPFC initiates a dPFC–NAcore–VP series circuit that mediates cocaine-induced drug-seeking behavior. Key words: cocaine; dopamine; glutamate; self-administration; craving; Reinstatement One of the most insidious problems associated with chronic drug use is the tendency for users to relapse even after extended periods of drugs abstinence. Many types of stimuli can increase reports of craving and subsequent relapse in drug addicts, including reexposure to the drug itself, stress, and cocaine-associated cues (Jaffe et al., 1989; Childress et al., 1999), and animal Reinstatement models of drug-seeking behavior have been established to evaluate the neurobiology of Reinstatement and relapse (Shaha
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limbic and motor circuitry underlying footshock induced Reinstatement of cocaine seeking behavior
The Journal of Neuroscience, 2004Co-Authors: Krista Mcfarland, Susan B Davidge, Christopher C Lapish, Peter W KalivasAbstract:The role of limbic, cortical, and striatal circuitry in a footshock Reinstatement model of relapse to cocaine seeking was evaluated. Transient inhibition of the central extended amygdala [CEA; including the central nucleus of the amygdala (CN), ventral bed nucleus of the stria terminalis (BNSTv), and nucleus accumbens shell (NAshell)], ventral tegmental area (VTA), and motor circuitry [including the dorsal prefrontal cortex (PFCd), nucleus accumbens core (NAcore), and ventral pallidum (VP)] blocked the ability of footshock stress to reinstate lever pressing previously associated with cocaine delivery. However, inhibition of the basolateral amygdala, mediodorsal nucleus of the thalamus, or the ventral prefrontal cortex had no effect on drug-seeking behavior. These data suggest that footshock stress activates limbic circuitry of the CEA that, via the VTA, activates motor output circuitry responsible for producing lever press responding. Consistent with this notion, the D1/D2 dopamine receptor antagonist fluphenazine blocked footshock-induced Reinstatement when infused into the PFCd. Further, inhibition of the NAshell blocked a footshock-induced increase in dopamine within the PFC and concomitantly blocked Reinstatement responding. Also supporting the idea of a CEA-VTA-motor circuit in stress-induced Reinstatement of cocaine seeking, inactivation of the PFCd was shown to block stress-induced glutamate release within the NAcore while concurrently inhibiting Reinstatement responding. Taken together, these data suggest that footshock activates limbic circuitry in the CEA, which in turn activates a VTA dopamine projection to the PFCd. The rise in dopamine within the PFCd initiates Reinstatement via a glutamatergic projection to the NAcore.
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brain circuitry and the Reinstatement of cocaine seeking behavior
Psychopharmacology, 2003Co-Authors: Peter W Kalivas, Krista McfarlandAbstract:Recent studies have attempted to identify the neuroanatomical substrates underlying primed Reinstatement of drug-seeking behavior. Identification of neuronal substrates will provide a logical rationale for designing pharmacological interventions in treating drug relapse. The objective was to identify brain circuitry that is shared between cue-, drug- and stress-primed Reinstatement, as well as identifying aspects of brain circuitry that are distinct for each stimulus modality. The resulting circuit offers theoretical interpretations for consideration in future studies. Aspects of the circuitry mediating Reinstatement can be identified with reasonable confidence. The role of the basolateral amygdala in cue-primed Reinstatement, the role of the ventral tegmental area in drug-primed Reinstatement and the role of adrenergic innervation of the extended amygdala in stress-primed Reinstatement are well characterized. Also, all three modes for priming Reinstatement may converge on the anterior cingulate cortex and have a final common output through the core of the nucleus accumbens. Lacunae in our understanding of the circuit were identified, especially with regard to how stress priming is conveyed from the extended amygdala to the shared anterior cingulate accumbens core circuit. The proposed convergence of priming stimuli into the glutamatergic projection from anterior cingulate to the accumbens core combined with the changes in glutamate transmission and signaling that accompany repeated psychostimulant administration points to the potential value of pharmacological agents that manipulate glutamate release or postsynaptic glutamate receptor signaling and trafficking in treating primed relapse in addicts.
Lin Lu - One of the best experts on this subject based on the ideXlab platform.
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region specific effects of brain corticotropin releasing factor receptor type 1 blockade on footshock stress or drug priming induced Reinstatement of morphine conditioned place preference in rats
Psychopharmacology, 2006Co-Authors: Jishi Wang, Qin Fang, Lin LuAbstract:Systemic injections of the selective corticotropin-releasing factor 1 (CRF1) receptor antagonist CP-154,526 attenuate footshock-stress-induced Reinstatement of heroin and cocaine seeking and morphine conditioned place preference (CPP). Intracranial injections of the nonselective CRF receptor antagonist d-Phe-CRF into the bed nucleus of the stria terminalis (BNST), but not the amygdala, attenuate footshock-induced Reinstatement of cocaine seeking. However, the brain sites involved in the effect of CP-154,526 on footshock-induced Reinstatement of opiate seeking are unknown. We used a CPP version of the Reinstatement model to examine the role of CRF1 receptors in the BNST, amygdala, and nucleus accumbens (NAc) in footshock- or drug-priming-induced Reinstatement of extinguished morphine CPP. Rats acquired morphine CPP over a period of 8 days during which they were given four morphine (10 mg/kg s.c.) and four saline injections and were subsequently confined to distinct chambers for 50 min. Subsequently, the morphine CPP was extinguished in 14 daily sessions during which rats were given saline injections and given access to both the saline- and morphine-paired chambers. The rats were then tested for Reinstatement of morphine CPP induced by priming injections of morphine (0 or 3.0 mg/kg s.c.) or by exposure to intermittent footshock (15 min, 0.5 mA). Prior to the test sessions, the rats were given intracranial injections of CP-154,526 (1.0 μg) or vehicle into the BNST, amygdala, or NAc. CP-154,526 injections into the BNST, but not the amygdala or NAc, attenuated footshock-stress-induced Reinstatement of morphine CPP. In contrast, CP-154,526 injections into the amygdala or NAc, but not the BNST, attenuated morphine-priming-induced Reinstatement of morphine CPP. The present results demonstrate dissociable roles of CRF1 receptors in the BNST, amygdala, and NAc in footshock-stress- vs morphine-priming-induced Reinstatement of drug CPP.
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the Reinstatement model of drug relapse history methodology and major findings
Psychopharmacology, 2003Co-Authors: Yavin Shaham, Lin Lu, Uri Shalev, Jane StewartAbstract:Rational and objectives. The Reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of Reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate Reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced Reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in Reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat Reinstatement model provides a suitable preclinical model of relapse to drug taking.
Jennifer M Bossert - One of the best experts on this subject based on the ideXlab platform.
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role of corticostriatal circuits in context induced Reinstatement of drug seeking
Brain Research, 2015Co-Authors: Nathan J Marchant, Yavin Shaham, Konstantin Kaganovsky, Jennifer M BossertAbstract:Drug addiction is characterized by persistent relapse vulnerability during abstinence. In abstinent drug users, relapse is often precipitated by re-exposure to environmental contexts that were previously associated with drug use. This clinical scenario is modeled in preclinical studies using the context-induced Reinstatement procedure, which is based on the ABA renewal procedure. In these studies, context-induced Reinstatement of drug seeking is reliably observed in laboratory animals that were trained to self-administer drugs abused by humans. In this review, we summarize neurobiological findings from preclinical studies that have focused on the role of corticostriatal circuits in context-induced Reinstatement of heroin, cocaine, and alcohol seeking. We also discuss neurobiological similarities and differences in the corticostriatal mechanisms of context-induced Reinstatement across these drug classes. We conclude by briefly discussing future directions in the study of context-induced relapse to drug seeking in rat models. Our main conclusion from the studies reviewed is that there are both similarities (accumbens shell, ventral hippocampus, and basolateral amygdala) and differences (medial prefrontal cortex and its projections to accumbens) in the neural mechanisms of context-induced Reinstatement of cocaine, heroin, and alcohol seeking.
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context induced Reinstatement of methamphetamine seeking is associated with unique molecular alterations in fos expressing dorsolateral striatum neurons
The Journal of Neuroscience, 2015Co-Authors: F J Rubio, Qingrong Liu, Fabio C Cruz, Rodrigo M Leao, Brandon L Warren, Sarita Kambhampati, K R Babin, Kylie B Mcpherson, Raffaello Cimbro, Jennifer M BossertAbstract:Context-induced Reinstatement of drug seeking is a well established animal model for assessing the neural mechanisms underlying context-induced drug relapse, a major factor in human drug addiction. Neural activity in striatum has previously been shown to contribute to context-induced Reinstatement of heroin, cocaine, and alcohol seeking, but not yet for methamphetamine seeking. In this study, we found that context-induced Reinstatement of methamphetamine seeking increased expression of the neural activity marker Fos in dorsal but not ventral striatum. Reversible inactivation of neural activity in dorsolateral but not dorsomedial striatum using the GABA agonists muscimol and baclofen decreased context-induced Reinstatement. Based on our previous findings that Fos-expressing neurons play a critical role in conditioned drug effects, we assessed whether context-induced Reinstatement was associated with molecular alterations selectively induced within context-activated Fos-expressing neurons. We used fluorescence-activated cell sorting to isolate Reinstatement-activated Fos-positive neurons from Fos-negative neurons in dorsal striatum and used quantitative PCR to assess gene expression within these two populations of neurons. Context-induced Reinstatement was associated with increased expression of the immediate early genes Fos and FosB and the NMDA receptor subunit gene Grin2a in only Fos-positive neurons. RNAscope in situ hybridization confirmed that Grin2a, as well as Grin2b, expression were increased in only Fos-positive neurons from dorsolateral, but not dorsomedial, striatum. Our results demonstrate an important role of dorsolateral striatum in context-induced Reinstatement of methamphetamine seeking and that this Reinstatement is associated with unique gene alterations in Fos-expressing neurons.
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the Reinstatement model of drug relapse recent neurobiological findings emerging research topics and translational research
Psychopharmacology, 2013Co-Authors: Jennifer M Bossert, Nathan J Marchant, Donna J Calu, Yavin ShahamAbstract:Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the Reinstatement model. In this model, Reinstatement of drug seeking by drug priming, drug cues or contexts, or certain stressors is assessed following drug self-administration training and subsequent extinction of the drug-reinforced responding. In this review, we first summarize recent (2009–present) neurobiological findings from studies using the Reinstatement model. We then discuss emerging research topics, including the impact of interfering with putative reconsolidation processes on cue- and context-induced Reinstatement of drug seeking, and similarities and differences in mechanisms of Reinstatement across drug classes. We conclude by discussing results from recent human studies that were inspired by results from rat studies using the Reinstatement model. Main conclusions from the studies reviewed highlight: (1) the ventral subiculum and lateral hypothalamus as emerging brain areas important for Reinstatement of drug seeking, (2) the existence of differences in brain mechanisms controlling Reinstatement of drug seeking across drug classes, (3) the utility of the Reinstatement model for assessing the effect of reconsolidation-related manipulations on cue-induced drug seeking, and (4) the encouraging pharmacological concordance between results from rat studies using the Reinstatement model and human laboratory studies on cue- and stress-induced drug craving.
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role of dorsal medial prefrontal cortex dopamine d1 family receptors in relapse to high fat food seeking induced by the anxiogenic drug yohimbine
Neuropsychopharmacology, 2011Co-Authors: Sunila G. Nair, Jennifer M Bossert, Charles L. Pickens, Brittany M Navarre, Carlo Cifani, Yavin ShahamAbstract:In humans, relapse to maladaptive eating habits during dieting is often provoked by stress. In rats, the anxiogenic drug yohimbine, which causes stress-like responses in both humans and nonhumans, reinstates food seeking in a relapse model. In this study, we examined the role of medial prefrontal cortex (mPFC) dopamine D1-family receptors, previously implicated in stress-induced Reinstatement of drug seeking, in yohimbine-induced Reinstatement of food seeking. We trained food-restricted rats to lever press for 35% high-fat pellets every other day (9–15 sessions, 3 h each); pellet delivery was accompanied by a discrete tone-light cue. We then extinguished operant responding for 10–16 days by removing the pellets. Subsequently, we examined the effect of yohimbine (2 mg/kg, i.p.) on Reinstatement of food seeking and Fos (a neuronal activity marker) induction in mPFC. We then examined the effect of systemic injections of the D1-family receptor antagonist SCH23390 (10 μg/kg, s.c.) on yohimbine-induced Reinstatement and Fos induction, and that of mPFC SCH23390 (0.5 and 1.0 μg/side) injections on this Reinstatement. Yohimbine-induced Reinstatement was associated with strong Fos induction in the dorsal mPFC and with weaker Fos induction in the ventral mPFC. Systemic SCH23390 injections blocked both yohimbine-induced Reinstatement and mPFC Fos induction. Dorsal, but not ventral, mPFC injections of SCH23390 decreased yohimbine-induced Reinstatement of food seeking. In addition, dorsal mPFC SCH23390 injections decreased pellet-priming-induced Reinstatement, but had no effect on ongoing high-fat pellet self-administration or discrete-cue-induced Reinstatement. Results indicate a critical role of dorsal mPFC dopamine D1-family receptors in stress-induced relapse to palatable food seeking, as well as relapse induced by acute re-exposure to food taste, texture, and smell.
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peptide yy3 36 decreases Reinstatement of high fat food seeking during dieting in a rat relapse model
The Journal of Neuroscience, 2007Co-Authors: Udi E Ghitza, Jennifer M Bossert, Sunila G. Nair, Sam A Golden, Sarah M Gray, Jamie L Uejima, Yavin ShahamAbstract:A major problem in treating obesity is high rates of relapse to maladaptive food-taking habits during dieting. This relapse is often provoked by acute re-exposure to palatable food, food-associated cues, or stress. We used a Reinstatement model, commonly used to study relapse to abused drugs, to explore the effect of peptide YY3-36 (PYY3-36) on Reinstatement of high-fat (35%, 45 mg pellets) food seeking induced by acute exposure to the pellets (pellet priming), a cue previously associated with pellet delivery (pellet cue), or yohimbine (2 mg/kg, a pharmacological stressor). Rats were placed on a restricted diet (16 g of chow per day) and lever-pressed for the pellets for 9-12 sessions (6 h/d, every 48 h); pellet delivery was paired with a tone-light cue. They were then given 10-20 extinction sessions wherein lever presses were not reinforced with the pellets and subsequently tested for Reinstatement of food seeking. Systemic PYY3-36 injections (100-200 microg/kg) decreased pellet priming- and pellet cue-induced Reinstatement of food seeking but not yohimbine-induced Reinstatement. Arcuate nucleus (Arc) injections of PYY3-36 (0.4 microg per side) decreased pellet priming-induced Reinstatement. The attenuation of pellet priming-induced Reinstatement by systemic PYY3-36 was reversed by systemic (2 mg/kg) but not Arc (0.5 microg per side) injections of the Y2 receptor antagonist BIIE0246. Arc PYY3-36 injections did not decrease pellet cue-induced Reinstatement. Finally, systemic PYY3-36 injections had minimal effects on ongoing food self-administration or heroin priming- or heroin cue-induced Reinstatement of heroin seeking. These data identify an effect of systemic PYY3-36 on relapse to food seeking that is independent of Y2 receptor activation in Arc and suggest that PYY3-36 should be considered for the treatment of relapse to maladaptive food-taking habits during dieting.
Jane Stewart - One of the best experts on this subject based on the ideXlab platform.
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toward a model of drug relapse an assessment of the validity of the Reinstatement procedure
Psychopharmacology, 2006Co-Authors: David H Epstein, Jane Stewart, Kenzie L Preston, Yavin ShahamAbstract:The Reinstatement model is widely used to study relapse to drug addiction. However, the model’s validity is open to question. We assess the Reinstatement model in terms of criterion and construct validity. We find that the Reinstatement model has adequate criterion validity in the broad sense of the term, as evidenced by the fact that Reinstatement in laboratory animals is induced by conditions reported to provoke relapse in humans. The model’s criterion validity in the narrower sense, as a medication screen, seems promising for relapse to heroin, nicotine, and alcohol. For relapse to cocaine, criterion validity has not yet been established primarily because clinical studies have examined medication’s effects on reductions in cocaine intake rather than relapse during abstinence. The model’s construct validity faces more substantial challenges and is yet to be established, but we argue that some of the criticisms of the model in this regard may have been overstated.
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the Reinstatement model of drug relapse history methodology and major findings
Psychopharmacology, 2003Co-Authors: Yavin Shaham, Lin Lu, Uri Shalev, Jane StewartAbstract:Rational and objectives. The Reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of Reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate Reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced Reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in Reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat Reinstatement model provides a suitable preclinical model of relapse to drug taking.
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the Reinstatement model of drug relapse history methodology and major findings
Psychopharmacology, 2003Co-Authors: Yavin Shaham, Uri Shalev, Harriet De Wit, Jane StewartAbstract:The Reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of Reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate Reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced Reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in Reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat Reinstatement model provides a suitable preclinical model of relapse to drug taking. The data derived from studies using the Reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced Reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced Reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on Reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce Reinstatement in laboratory animals and those that provoke relapse in humans.
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A role for the prefrontal cortex in stress- and cocaine-induced Reinstatement of cocaine seeking in rats.
Psychopharmacology, 2002Co-Authors: Nancy Capriles, Demetra Rodaros, Robert E Sorge, Jane StewartAbstract:It is well established that stress induces Reinstatement of drug seeking in an animal model of relapse. Here we studied the role of the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) in foot-shock stress-induced Reinstatement of cocaine seeking. Groups of rats were trained to self-administer cocaine (0.5 mg/kg per infusion, i.v., 3 h/day for 9 days) and after ten drug-free days were exposed to extinction and Reinstatement test sessions. Each 60 min of extinction was separated by a 30-min time-out period after which the lever and stimulus lights were reintroduced. Rats were given four 1-h extinction sessions on day 1 and then on subsequent days were given two to three 1-h extinction sessions that were followed by a 3-h test for Reinstatement. Tests were run every 48 h. In one set of experiments, the effects of inactivation of the prelimbic (PL), infralimbic (IL) or OFC by tetrodotoxin (TTX, 5 ng/0.5 micro l per side) on Reinstatement induced by foot shock (5 min, intermittent, 1 mA) or priming injections of cocaine (20 mg/kg, i.p.) were determined. In a second set, the effects of infusions of the D1-like and D2-like dopamine receptor antagonists (SCH 23390 and raclopride) were studied using the same methods. TTX infusions into the PL cortex blocked both foot shock and cocaine-induced Reinstatement. TTX into OFC attenuated foot-shock-induced, but not cocaine-induced Reinstatement. Infusions into IL were ineffective. Infusions of SCH 22390 (0.25 micro g/0.5 micro l per side) into either PL or OFC blocked foot-shock-induced Reinstatement, but infusions into PL had no effect on cocaine-induced Reinstatement. Raclopride (5 micro g/0.5 micro l per side) had no effect on foot-shock-induced Reinstatement in either PL or OFC or on cocaine-induced Reinstatement when infused into PL. Neither TTX nor SCH23390 infusions into PL or OFC had any effect on lever pressing for sucrose. These results suggest that the PL and OFC regions form part of the circuitry mediating the effects of foot shock stress on Reinstatement of drug seeking and that the PL region may be a common pathway for cue, drug and foot-shock stress-induced Reinstatement of drug seeking.
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a role for the bed nucleus of the stria terminalis but not the amygdala in the effects of corticotropin releasing factor on stress induced Reinstatement of cocaine seeking
The Journal of Neuroscience, 1999Co-Authors: Suzanne Erb, Jane StewartAbstract:We have shown that intracerebroventricular administration of the corticotropin-releasing factor (CRF) receptor antagonist D-Phe CRF(12-41), blocks footshock-induced Reinstatement of drug seeking in cocaine-trained rats. We now report that D-Phe acts in the bed nucleus of the stria terminalis (BNST), and not in the amygdala, to block footshock-induced Reinstatement of cocaine seeking. In addition, CRF injections in the BNST, and not in the amygdala, are sufficient to reinstate cocaine seeking. Rats were trained to self-administer cocaine intravenously on a fixed ratio (FR-1) schedule of reinforcement. After 5 drug-free days, animals were returned to the self-administration chambers and given daily extinction and Reinstatement test sessions. To test the effects of D-Phe CRF(12-41) on stress-induced Reinstatement, rats were pretreated with vehicle or D-Phe in either the BNST (10 or 50 ng per side) or amygdala (50 or 500 ng per side) before being exposed to 15 min of intermittent footshock stress. To test whether injections of CRF itself could induce Reinstatement, rats were given vehicle or CRF in either the BNST (100 or 300 ng per side) or amygdala (300 ng per side) 15 min before the session. Injections of D-Phe into the BNST completely blocked footshock-induced Reinstatement of cocaine seeking; injections of CRF itself in this structure induced Reinstatement. Injections of these compounds into the amygdala were without effect. These findings suggest that activation of CRF receptors in the BNST, but not in the amygdala, is critical for footshock-induced Reinstatement of cocaine seeking.
