| 1. |
- Bazov, Igor, 1973-, et al.
(författare)
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Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.
- 2018
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Ingår i: Molecular Neurobiology. - : Springer. - 0893-7648 .- 1559-1182. ; 55:8, s. 7049-7061
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Tidskriftsartikel (refereegranskat)abstract
- Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.
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| 2. |
- Bilbao, Ainhoa, et al.
(författare)
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A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption : Evidence from Humanized Mice.
- 2015
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 77:10, s. 850-858
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: It has been proposed that therapeutic responses to naltrexone in alcoholism are moderated by variation at the mu-opioid receptor gene locus (OPRM1). This remains controversial because human results vary and no prospectively genotyped studies have been reported. We generated humanized mice carrying the respective human OPRM1 A118G alleles. Here, we used this model system to examine the role of OPRM1 A118G variation for opioid antagonist effects on alcohol responses.METHODS: Effects of naltrexone on alcohol reward were examined using intracranial self-stimulation. Effects of naltrexone or nalmefene on alcohol intake were examined in continuous access home cage two-bottle free-choice drinking and operant alcohol self-administration paradigms.RESULTS: Alcohol lowered brain stimulation reward thresholds in 118GG mice in a manner characteristic of rewarding drugs, and this effect was blocked by naltrexone. Brain stimulation reward thresholds were unchanged by alcohol or naltrexone in 118AA mice. In the home cage, increased alcohol intake emerged in 118GG mice with increasing alcohol concentrations and was 33% higher at 17% alcohol. At this concentration, naltrexone selectively suppressed alcohol intake in 118GG animals to a level virtually identical to that of 118AA mice. No effect of naltrexone was found in the latter group. Similarly, both naltrexone and nalmefene were more effective in suppressing operant alcohol self-administration in 118GG mice.CONCLUSIONS: In a model that allows close experimental control, OPRM1 A118G variation robustly moderates effects of opioid antagonism on alcohol reward and consumption. These findings strongly support a personalized medicine approach to alcoholism treatment that takes into account OPRM1 genotype.
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| 3. |
- Bilbao, Ainhoa, et al.
(författare)
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Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences; 1999. - 0027-8424 .- 1091-6490. ; 105:45, s. 17549-17554
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Tidskriftsartikel (refereegranskat)abstract
- The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription.
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| 4. |
- Domi, Esi, et al.
(författare)
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Genetic Deletion of Neuronal PPAR gamma Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPAR gamma Function
- 2016
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Ingår i: JOURNAL OF NEUROSCIENCE. - : SOC NEUROSCIENCE. - 0270-6474. ; 36:50, s. 12611-12623
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Tidskriftsartikel (refereegranskat)abstract
- PPAR gamma is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPAR gamma is activated by thiazolidinediones such as pioglitazone and is targeted to treat insulin resistance. PPAR gamma is densely expressed in brain areas involved in regulation of motivational and emotional processes. Here, we investigated the role of PPAR gamma in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPAR gamma by pioglitazone did not affect basal anxiety, but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPAR gamma (PPAR gamma(NestinCre)), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPAR gamma antagonist, elicited a marked anxiogenic response in PPAR gamma wild-type (WT), but not in PPAR gamma(NestinCre) knock-out (KO) mice. Using c-Fos immunohistochemistry, we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala (AMY) and the hippocampus (HIPP) of PPAR gamma(NestinCre) KO mice compared with WT mice. No differences were found between WT and KO mice in hypothalamic regions responsible for hormonal response to stress or in blood corticosterone levels. Microinjection of pioglitazone into the AMY, but not into the HIPP, abolished the anxiogenic response elicited by acute stress. Results also showed that, in both regions, PPAR gamma colocalizes with GABAergic cells. These findings demonstrate that neuronal PPAR gamma is involved the regulation of the stress response and that the AMY is a key substrate for the anxiolytic effect of PPAR gamma
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| 5. |
- Dong, Li, et al.
(författare)
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Effects of the Circadian Rhythm Gene Period 1 (Per1) on Psychosocial Stress-Induced Alcohol Drinking
- 2011
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 168:10, s. 1090-1098
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Circadian and stress-response systems mediate environmental changes that affect alcohol drinking. Psychosocial stress is an environmental risk factor for alcohol abuse. Circadian rhythm gene period 1(Per1) is targeted by stress hormones and is transcriptionally activated in corticotropin releasing factor-expressing cells. The authors hypothesized that Per1 is involved in integrating stress response and circadian rhythmicity and explored its relevance to alcohol drinking. Method: In mice, the effects of stress on ethanol intake in mPer1-mutant and wild-type mice were assessed. In humans, single nucleotide polymorphisms (SNPs) in hPer1 were tested for association with alcohol drinking behavior in 273 adolescents and an adult case-control sample of 1,006 alcohol-dependent patients and 1,178 comparison subjects. In vitro experiments were conducted to measure genotype-specific expression and transcription factor binding to hPer1. Results: The mPer1-mutant mice showed enhanced alcohol consumption in response to social defeat stress relative to their wild-type littermates. An association with the frequency of heavy drinking in adolescents with the hPer1 promoter SNP rs3027172 and with psychosocial adversity was found. There was significant interaction between the rs3027172 genotype and psychosocial adversity on this drinking measure. In a confirmatory analysis, association of hPer1 rs3027172 with alcohol dependence was shown. Cortisol-induced transcriptional activation of hPer1 was reduced in human B-lymphoblastoid cells carrying the risk genotype of rs3027172. Binding affinity of the transcription factor Snail1 to the risk allele of the hPer1 SNP rs3027172 was also reduced. Conclusions: The findings indicate that the hPer1 gene regulates alcohol drinking behavior during stressful conditions and provide evidence for underlying neurobiological mechanisms.
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| 6. |
- Drude, Natascha Ingrid, et al.
(författare)
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Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research : a multi-stakeholder workshop report
- 2022
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Ingår i: Translational Medicine Communications. - : Springer Nature. - 2396-832X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solution-oriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory.
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| 7. |
- Ekhtiari, Hamed, et al.
(författare)
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A methodological checklist for fMRI drug cue reactivity studies : development and expert consensus
- 2022
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Ingår i: Nature Protocols. - : Nature Portfolio. - 1754-2189 .- 1750-2799. ; 17:3, s. 567-595
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Tidskriftsartikel (refereegranskat)abstract
- Cue reactivity measured by functional magnetic resonance imaging is used in studies of substance-use disorders. This Consensus Statement is the result of a Delphi process to arrive at parameters that should be reported in describing these studies. Cue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participants characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work are difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting and review the FDCR literature to assess the reporting of items that are deemed important. Forty-five FDCR scientists from around the world participated in this study. First, an initial checklist of items deemed important in FDCR studies was developed by several members of the Enhanced NeuroImaging Genetics through Meta-Analyses (ENIGMA) Addiction working group on the basis of a systematic review. Using a modified Delphi consensus method, all experts were asked to comment on, revise or add items to the initial checklist, and then to rate the importance of each item in subsequent rounds. The reporting status of the items in the final checklist was investigated in 108 recently published FDCR studies identified through a systematic review. By the final round, 38 items reached the consensus threshold and were classified under seven major categories: Participants Characteristics, General fMRI Information, General Task Information, Cue Information, Craving Assessment Inside Scanner, Craving Assessment Outside Scanner and Pre- and Post-Scanning Considerations. The review of the 108 FDCR papers revealed significant gaps in the reporting of the items considered important by the experts. For instance, whereas items in the General fMRI Information category were reported in 90.5% of the reviewed papers, items in the Pre- and Post-Scanning Considerations category were reported by only 44.7% of reviewed FDCR studies. Considering the notable and sometimes unexpected gaps in the reporting of items deemed to be important by experts in any FDCR study, the protocols could benefit from the adoption of reporting standards. This checklist, a living document to be updated as the field and its methods advance, can help improve experimental design, reporting and the widespread understanding of the FDCR protocols. This checklist can also provide a sample for developing consensus statements for protocols in other areas of task-based fMRI.
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| 8. |
- Engblom, David, et al.
(författare)
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Glutamate receptors on dopamine neurons control the persistence of cocaine seeking
- 2008
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Ingår i: Neuron. - : Elsevier Science B.V., Amsterdam.. - 0896-6273 .- 1097-4199. ; 59:3, s. 497-508
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Tidskriftsartikel (refereegranskat)abstract
- Cocaine strengthens excitatory synapses onto midbrain dopamine neurons through the synaptic delivery of GluR1-containing AMPA receptors. This cocaine-evoked plasticity depends on NMDA receptor activation, but its behavioral significance in the context of addiction remains elusive. Here, we generated mice lacking the GluR1, GluR2, or NR1 receptor subunits selectively in dopamine neurons. We report that in midbrain slices of cocaine-treated mice, synaptic transmission was no longer strengthened when GluR1 or NR1 was abolished, while in the respective mice the drug still induced normal conditioned place preference and locomotor sensitization. In contrast, extinction of drug-seeking behavior was absent in mice lacking GluR1, while in the NR1 mutant mice reinstatement was abolished. In conclusion, cocaine-evoked synaptic plasticity does not mediate concurrent short-term behavioral effects of the drug but may initiate adaptive changes eventually leading to the persistence of drug-seeking behavior.
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| 9. |
- Hansson, Anita C., et al.
(författare)
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Oxytocin Reduces Alcohol Cue-Reactivity in Alcohol-Dependent Rats and Humans
- 2018
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Ingår i: Neuropsychopharmacology. - : NATURE PUBLISHING GROUP. - 0893-133X .- 1740-634X. ; 43:6, s. 1235-1246
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Tidskriftsartikel (refereegranskat)abstract
- Approved pharmacological treatments for alcohol use disorder are limited in their effectiveness, and new drugs that can easily be translated into the clinic are warranted. One of those candidates is oxytocin because of its interaction with several alcohol-induced effects. Alcoholdependent rats as well as post-mortem brains of human alcoholics and controls were analyzed for the expression of the oxytocin system by qRT-PCR, in situ hybridizaton, receptor autoradiography ([(125)l]OVTA binding), and immunohistochemistry. Alcohol self administration and cue-induced reinstatement behavior was measured after intracerebroventicular injection of 10 nM oxytocin in dependent rats. Here we show a pronounced upregulation of oxytocin receptors in brain tissues of alcohol dependent rats and deceased alcoholics, primarily in frontal and striatal areas. This upregulation stems most likely from reduced oxytocin expression in hypothalamic nuclei. Pharmacological validaton showed that oxytocin reduced cue-induced reinstatement response in dependent rats-an effect that was not observed in nondependent rats. Finally, a clinical pilot study (German clinical trial number DRKS00009253) using functional magnetic resonance imaging in heavy social male drinkers showed that intranasal oxytocin (24 IU) decreased neural cue-reactivity in brain networks similar to those detected in dependent rats and humans with increased oxytocin receptor expression. These studies suggest that oxytocin might be used as an anticraving medication and thus may positvely affect treatment outcomes in alcoholics.
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| 10. |
- Mameli, Manuel, et al.
(författare)
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Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc
- 2009
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Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 12:8, s. 1036-U108
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Tidskriftsartikel (refereegranskat)abstract
- Addictive drugs hijack mechanisms of learning and memory that normally underlie reinforcement of natural rewards and induce synaptic plasticity of glutamatergic transmission in the mesolimbic dopamine (DA) system. In the ventral tegmental area (VTA), a single exposure to cocaine efficiently triggers NMDA receptor-dependent synaptic plasticity in DA neurons, whereas plasticity in the nucleus accumbens (NAc) occurs only after repeated injections. Whether these two forms of plasticity are independent or hierarchically organized remains unknown. We combined ex vivo electrophysiology in acute brain slices with behavioral assays modeling drug relapse in mice and found that the duration of the cocaine-evoked synaptic plasticity in the VTA is gated by mGluR1. Overriding mGluR1 in vivo made the potentiation in the VTA persistent. This led to synaptic plasticity in the NAc, which contributes to cocaine-seeking behavior after protracted withdrawal. Impaired mGluR1 function in vulnerable individuals could represent a first step in the recruitment of the neuronal network that underlies drug addiction.
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