| 1. |
- Domi, Esi, et al.
(författare)
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A neural substrate of compulsive alcohol use
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science. - 2375-2548. ; 7:34
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol intake remains controlled in a majority of users but becomes "compulsive," i.e., continues despite adverse consequences, in a minority who develop alcohol addiction. Here, using a footshock-punished alcohol self-administration procedure, we screened a large population of outbred rats to identify those showing compulsivity operationalized as punishment-resistant self-administration. Using unsupervised clustering, we found that this behavior emerged as a stable trait in a subpopulation of rats and was associated with activity of a brain network that included central nucleus of the amygdala (CeA). Activity of PKC delta(+) inhibitory neurons in the lateral subdivision of CeA (CeL) accounted for similar to 75% of variance in punishment-resistant alcohol taking. Activity-dependent tagging, followed by chemogenetic inhibition of neurons activated during punishment-resistant self-administration, suppressed alcohol taking, as did a virally mediated shRNA knockdown of PKC delta in CeA. These findings identify a previously unknown mechanism for a core element of alcohol addiction and point to a novel candidate therapeutic target.
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| 2. |
- Epstein, David H., et al.
(författare)
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Science-Based Actions Can Help Address the Opioid Crisis
- 2018
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Ingår i: TIPS - Trends in Pharmacological Sciences. - : ELSEVIER SCIENCE LONDON. - 0165-6147 .- 1873-3735. ; 39:11, s. 911-916
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The epidemic of addiction and over-dose is real. Addiction among pain patients accounts for only a small proportion but a large number. Scientific opinion leaders can be most effective on two fronts, each relatively low-tech: dissemination and oversight of empirically established treatments, and promulgation of social-science-based strategies for population-level prevention.
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| 3. |
- Fredriksson, Ida, et al.
(författare)
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Animal Models of Drug Relapse and Craving after Voluntary Abstinence: A Review
- 2021
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Ingår i: Pharmacological Reviews. - : AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS. - 0031-6997 .- 1521-0081. ; 73:3, s. 1050-1083
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Forskningsöversikt (refereegranskat)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 drugs 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.
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| 4. |
- Fredriksson, Ida, et al.
(författare)
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Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence.
- 2020
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group. - 0893-133X .- 1740-634X. ; 45:5, s. 770-779
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Tidskriftsartikel (refereegranskat)abstract
- In the classical incubation of drug craving rat model, drug seeking is assessed after homecage forced abstinence. However, human abstinence is often voluntary because negative consequences of drug seeking outweigh the desire for the drug. Here, we developed a rat model of incubation of opioid craving after electric barrier-induced voluntary abstinence and determined whether the dopamine stabilizer (-)-OSU6162 would decrease this new form of incubation. We trained male and female rats to self-administer oxycodone (0.1 mg/kg/infusion, 6 h/day) for 14 days. We then exposed them to either homecage forced abstinence or voluntary abstinence induced by an electric barrier of increasing intensity near the drug-paired lever. On abstinence days 1, 15, or 30, we tested the rats for oxycodone seeking without shock and drug. We also examined the effect of (-)-OSU6162 (7.5 and 15 mg/kg) on oxycodone seeking on abstinence day 1 or after 15 days of either voluntary or forced abstinence. Independent of sex, the time-dependent increase in oxycodone seeking after cessation of opioid self-administration (incubation of opioid craving) was stronger after voluntary abstinence than after forced abstinence. In males, (-)-OSU6162 decreased incubated (day 15) but not non-incubated (day 1) oxycodone seeking after either voluntary or forced abstinence. In females, (-)-OSU6162 modestly decreased incubated oxycodone seeking after voluntary but not forced abstinence. Results suggest that voluntary abstinence induced by negative consequences of drug seeking can paradoxically potentiate opioid craving and relapse. We propose the dopamine stabilizer (-)-OSU6162 may serve as an adjunct pharmacological treatment to prevent relapse in male opioid users.
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| 5. |
- Fredriksson, Ida, et al.
(författare)
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Orbitofrontal cortex and dorsal striatum functional connectivity predicts incubation of opioid craving after voluntary abstinence
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 118:43
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Tidskriftsartikel (refereegranskat)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 selfadministration training (early abstinence) and after electric barrier exposure (late abstinence). We imaged their brains before selfadministration and during early and late abstinence. We analyzed changes in OFC functional connectivity induced by reward selfadministration 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.
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| 6. |
- Fredriksson, Ida, et al.
(författare)
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Role of ventral subiculum neuronal ensembles in incubation of oxycodone craving after electric barrier-induced voluntary abstinence
- 2023
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Ingår i: Science Advances. - : AMER ASSOC ADVANCEMENT SCIENCE. - 2375-2548. ; 9:2
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Tidskriftsartikel (refereegranskat)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, Daun020-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.
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| 7. |
- Heilig, Markus, et al.
(författare)
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Time to connect: bringing social context into addiction neuroscience
- 2016
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Ingår i: Nature Reviews Neuroscience. - : NATURE PUBLISHING GROUP. - 1471-003X .- 1471-0048. ; 17:9, s. 592-599
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Forskningsöversikt (refereegranskat)abstract
- Research on the neural substrates of drug reward, withdrawal and relapse has yet to be translated into significant advances in the treatment of addiction. One potential reason is that this research has not captured a common feature of human addiction: progressive social exclusion and marginalization. We propose that research aimed at understanding the neural mechanisms that link these processes to drug seeking and drug taking would help to make addiction neuroscience research more clinically relevant.
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| 8. |
- Negishi, Kenichiro, et al.
(författare)
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Relapse after electric barrier-induced voluntary abstinence: A review
- 2024
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Ingår i: Current Opinion in Neurobiology. - : CURRENT BIOLOGY LTD. - 0959-4388 .- 1873-6882. ; 86
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Tidskriftsartikel (refereegranskat)abstract
- 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 FDAapproved medications for relapse prevention. To address this translational gap, we and others have developed rat models of relapse after voluntary abstinence from drug selfadministration. 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 (timedependent 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.
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| 9. |
- Schank, Jesse R., et al.
(författare)
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Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L822429
- 2011
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Ingår i: Psychopharmacology. - : Springer. - 0033-3158 .- 1432-2072. ; 218:1, s. 111-119
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Genetic inactivation or pharmacological antagonism of neurokinin 1 (NK1) receptors blocks morphine and alcohol reward in rodents, while NK1 antagonism decreases alcohol craving in humans. The role of the NK1 system for relapse-like behavior has not previously been examined.OBJECTIVE: Divergence between human and rodent NK1 receptors has limited the utility of NK1 antagonists developed for the human receptor species for preclinical studies of addiction-related behaviors in rats. Here we used L822429, an NK1 antagonist specifically engineered to bind at high affinity to the rat receptor, to assess the effects of NK1 receptor antagonism on alcohol-seeking behaviors in rats.METHODS: L822429 (15 and 30 mg/kg) was used to examine effects of NK1 receptor antagonism on operant self-administration of 10% alcohol in 30-min daily sessions, as well as intermittent footshock stress- and cue-induced reinstatement of alcohol-seeking after extinction of lever responding.RESULTS: At the doses used, L822429 did not significantly affect alcohol self-administration or cue-induced reinstatement, but potently and dose dependently suppressed stress-induced reinstatement of alcohol seeking, with an essentially complete suppression at the highest dose. The effect of L822429 on stress-induced reinstatement was behaviorally specific. The drug had no effect on conditioned suppression of operant responding following fear conditioning, locomotor activity, or self-administration of a sucrose solution.CONCLUSIONS: To the degree that the reinstatement model provides a model of drug relapse, the results provide support for NK1 antagonism as a promising mechanism for pharmacotherapy of alcoholism, acting through suppression of stress-induced craving and relapse.
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| 10. |
- Venniro, Marco, et al.
(författare)
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Improving translation of animal models of addiction and relapse by reverse translation
- 2020
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Ingår i: Nature Reviews Neuroscience. - : NATURE RESEARCH. - 1471-003X .- 1471-0048. ; 21:11, s. 625-643
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Forskningsöversikt (refereegranskat)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 theDiagnostic 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. Recent advances in animal addiction models have emphasized translational challenges. In this Review, Venniro and colleagues introduce a reverse translational approach that may provide an ecologically relevant platform from which to discover new circuits, test new medications and improve translation.
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