| 1. |
- Schumann, Gunter, et al.
(författare)
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Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:17, s. 7119-7124
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of similar to 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Downregulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.
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| 2. |
- Baker, Maggie, et al.
(författare)
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Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques
- 2017
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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. ; 114:44, s. 11769-11774
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Tidskriftsartikel (refereegranskat)abstract
- Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to deter mine whether a gain-of-function nonsynonymous OXTR SNP inter acted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavior al differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.
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| 3. |
- 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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| 4. |
- 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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| 5. |
- Björk, Karl, et al.
(författare)
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Ethanol-induced activation of AKT and DARPP-32 in the mouse striatum mediated by opioid receptors
- 2010
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Ingår i: Addiction Biology. - : Wiley-Blackwell. - 1355-6215 .- 1369-1600. ; 15:3, s. 299-303
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Tidskriftsartikel (refereegranskat)abstract
- The reinforcing properties of ethanol are in part attributed to interactions between opioid and dopaminergic signaling pathways, but intracellular mediators of such interactions are poorly understood. Here we report that an acute ethanol challenge induces a robust phosphorylation of two key signal transduction kinases, AKT and DARPP-32, in the striatum of mice. Ethanol-induced AKT phosphorylation was blocked by the opioid receptor antagonist naltrexone but unaffected by blockade of dopamine D2 receptors via sulpiride. In contrast, DARPP-32 phosphorylation was abolished by both antagonists. These data suggest that ethanol acts via two distinct but potentially synergistic striatal signaling cascades. One of these is D2-dependent, while the other is not. These findings illustrate that pharmacology of ethanol reward is likely more complex than that for other addictive drugs.
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| 6. |
- Björk, Karl, et al.
(författare)
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β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol
- 2013
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Ingår i: Psychopharmacology. - : Springer. - 0033-3158 .- 1432-2072. ; 230:3, s. 439-449
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Tidskriftsartikel (refereegranskat)abstract
- RationaleThe rewarding effects of alcohol have been attributed to interactions between opioid and dopaminergic system within the mesolimbic reward pathway. We have previously shown that ablation of β-arrestin 2 (Arrb2), a crucial regulator of μ-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens.ObjectivesHere, we further investigated the role of Arrb2 in modulating alcohol-induced dopamine (DA) release and conditioned place preference (CPP). We also assessed the functional importance of Arrb2 for μ-opioid receptor surface expression and signaling following an acute alcohol challenge.MethodsAlcohol-evoked (0.375, 0.75, and 1.5 g/kg intraperitoneally) DA release was measured by in vivo microdialysis in the shell of nucleus accumbens. Reward was assessed by the CPP paradigm. Receptor function was assessed by μ-receptor binding and [35S]GTP-γ-S autoradiography.ResultsIn Arrb2 knockout mice accumbal DA levels reach maximum response at a lower dose compared to wild-type (wt) animals. In line with these results, Arrb2 knockout mice display increased CPP for alcohol as compared to wt mice. Finally, Arrb2 mutant mice display increased μ-opioid receptor signaling in the ventral and dorsal striatum and amygdala in response to a low dose of alcohol, indicating impaired desensitization mechanisms in these mice.ConclusionsOur results show that Arrb2 modulates the response to low doses of alcohol on various levels including μ-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors.
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| 7. |
- Blom, Elin S, et al.
(författare)
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Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain
- 2010
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Ingår i: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252 .- 2090-8024. ; 2011, s. 936580-
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Tidskriftsartikel (refereegranskat)abstract
- Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P < .05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis.
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| 8. |
- Caruso, Vanni, et al.
(författare)
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mRNA GPR162 changes are associated with decreased food intake in rat, and its human genetic variants with impairments in glucose homeostasis in two Swedish cohorts
- 2016
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Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 581:2, s. 139-145
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Tidskriftsartikel (refereegranskat)abstract
- G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating intercellular interactions of fundamental physiological importance for survival including regulation of food intake, blood pressure, and hormonal sensing signaling, among other roles. Homeostatic alterations in the physiological status of GPCRs are often associated with underlying causes of disease, and to date, several orphan GPCRs are still uncharacterized. Findings from our previous study demonstrate that the Rhodopsin family protein GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in hypothalamus, amygdala, and ventral tegmental area, regions strictly interconnected and involved in the regulation of energy homeostasis and hedonic feeding. In this study, we provide a further anatomical characterization of GPR162 in mouse brain via in situ hybridization as well as detailed mRNA expression in a panel of rat tissues complementing a specie-specific mapping of the receptor. We also provide an attempt to demonstrate a functional implication of GPR162 in food intake-related behavior via antisense knockdown studies. Furthermore, we performed human genetic studies in which for the first time, variants of the GPR162 gene were associated with impairments in glucose homeostasis.
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| 9. |
- Cippitelli, Andrea, et al.
(författare)
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Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking
- 2010
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Ingår i: Psychopharmacology. - : Springer. - 0033-3158 .- 1432-2072. ; 208:3, s. 417-426
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine.MATERIALS AND METHODS: NPY [5.0 or 10.0 mug/rat, intracerebroventricularly (ICV)] dose-dependently blocked the reinstatement of alcohol seeking induced by yohimbine (1.25 mg/kg, i.p.) but failed to significantly suppress the maintenance of alcohol self-administration. We then used c-fos expression mapping to examine neuronal activation following treatment with yohimbine or NPY alone or yohimbine following NPY pre-treatment.RESULTS AND DISCUSSION: The analysis was focused on a network of structures previously implicated in yohimbine-induced reinstatement, comprised of central (CeA) and basolateral (BLA) amygdala and the shell of the nucleus accumbens (Nc AccS). Within this network, both yohimbine and NPY potently induced neuronal activation, and their effects were additive, presumably indicating activation of excitatory and inhibitory neuronal populations, respectively.CONCLUSION: These results suggest that NPY selectively suppresses relapse to alcohol seeking induced by stressful events and support the NPY system as an attractive target for the treatment of alcohol addiction.
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| 10. |
- 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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| 11. |
- Harel, Maayan, et al.
(författare)
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Repetitive Transcranial Magnetic Stimulation in Alcohol Dependence : A Randomized, Double-Blind, Sham-Controlled Proof-of-Concept Trial Targeting the Medial Prefrontal and Anterior Cingulate Cortices
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier Science Inc. - 0006-3223 .- 1873-2402. ; 91:12, s. 1061-1069
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alcohol addiction is associated with a high disease burden, and treatment options are limited. In a proof-of-concept study, we used deep repetitive transcranial magnetic stimulation (dTMS) to target circuitry associated with the pathophysiology of alcohol addiction. We evaluated clinical outcomes and explored associated neural signatures using functional magnetic resonance imaging. METHODS: This was a double-blind, randomized, sham-controlled trial. A total of 51 recently abstinent treatment-seeking patients with alcohol use disorder (moderate to severe) were randomized to sham or active dTMS, using an H7 coil targeting midline frontocortical areas, including the medial prefrontal and anterior cingulate cortices. Treatment included 15 sessions over 3 weeks, followed by five sessions over 3 months of follow-up. Each session delivered 100 trains of 30 pulses at 10 Hz. The primary predefined outcome was reduction in percentage of heavy drinking days, obtained using timeline follow-back interviews. Secondary analyses included self-reports of craving, ethyl glucuronide in urine, and brain imaging measures. RESULTS: Both craving after treatment and percentage of heavy drinking days during follow-up were significantly lower in the active versus sham control group (percentage of heavy drinking days = 2.9 +/- 0.8% vs. 10.6 +/- 1.9%, p = .037). Active dTMS was associated with decreased resting-state functional connectivity of the dorsal anterior cingulate cortex with the caudate nucleus and decreased connectivity of the medial prefrontal cortex to the subgenual anterior cingulate cortex. CONCLUSIONS: We provide initial proof-of-concept for dTMS targeting midline frontocortical structures as a treatment for alcohol addiction. These data strongly support a rationale for a full-scale confirmatory multicenter trial. Therapeutic benefits of dTMS appear to be associated with persistent changes in brain network activity.
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| 12. |
- Heilig, Markus, et al.
(författare)
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Developing neuroscience-based treatments for alcohol addiction: A matter of choice?
- 2019
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Ingår i: Translational Psychiatry. - : NATURE PUBLISHING GROUP. - 2158-3188. ; 9
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Forskningsöversikt (refereegranskat)abstract
- Excessive alcohol use is the cause of an ongoing public health crisis, and accounts for -5% of global disease burden. A minority of people with recreational alcohol use develop alcohol addiction (hereafter equated with "alcohol dependence" or simply "alcoholism"), a condition characterized by a systematically biased choice preference for alcohol at the expense of healthy rewards, and continued use despite adverse consequences ("compulsivity"). Alcoholism is arguably the most pressing area of unmet medical needs in psychiatry, with only a small fraction of patients receiving effective, evidence-based treatments. Medications currently approved for the treatment of alcoholism have small effect sizes, and their clinical uptake is negligible. No mechanistically new medications have been approved since 2004, and promising preclinical results have failed to translate into novel treatments. This has contributed to a reemerging debate whether and to what extent alcohol addiction represents a medical condition, or reflects maladaptive choices without an underlying brain pathology. Here, we review this landscape, and discuss the challenges, lessons learned, and opportunities to retool drug development in this important therapeutic area.
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| 13. |
- Heilig, Markus, et al.
(författare)
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Translating the neuroscience of alcoholism into clinical treatments : from blocking the buzz to curing the blues
- 2010
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Ingår i: Neuroscience and Biobehavioral Reviews. - : Elsevier. - 0149-7634 .- 1873-7528. ; 35:2, s. 334-344
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential.
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| 14. |
- Johnstone, Andrea L., et al.
(författare)
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Dysregulation of the histone demethylase KDM6B in alcohol dependence is associated with epigenetic regulation of inflammatory signaling pathways
- 2021
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Ingår i: Addiction Biology. - : WILEY. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic enzymes oversee long-term changes in gene expression by integrating genetic and environmental cues. While there are hundreds of enzymes that control histone and DNA modifications, their potential roles in substance abuse and alcohol dependence remain underexplored. A few recent studies have suggested that epigenetic processes could underlie transcriptomic and behavioral hallmarks of alcohol addiction. In the present study, we sought to identify epigenetic enzymes in the brain that are dysregulated during protracted abstinence as a consequence of chronic and intermittent alcohol exposure. Through quantitative mRNA expression analysis of over 100 epigenetic enzymes, we identified 11 that are significantly altered in alcohol-dependent rats compared with controls. Follow-up studies of one of these enzymes, the histone demethylase KDM6B, showed that this enzyme exhibits region-specific dysregulation in the prefrontal cortex and nucleus accumbens of alcohol-dependent rats. KDM6B was also upregulated in the human alcoholic brain. Upregulation of KDM6B protein in alcohol-dependent rats was accompanied by a decrease of trimethylation levels at histone H3, lysine 27 (H3K27me3), consistent with the known demethylase specificity of KDM6B. Subsequent epigenetic (chromatin immunoprecipitation [ChIP]-sequencing) analysis showed that alcohol-induced changes in H3K27me3 were significantly enriched at genes in the IL-6 signaling pathway, consistent with the well-characterized role of KDM6B in modulation of inflammatory responses. Knockdown of KDM6B in cultured microglial cells diminished IL-6 induction in response to an inflammatory stimulus. Our findings implicate a novel KDM6B-mediated epigenetic signaling pathway integrated with inflammatory signaling pathways that are known to underlie the development of alcohol addiction.
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| 15. |
- Mahmoud, Saifeldin, et al.
(författare)
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Pharmacological consequence of the A118G μ opioid receptor polymorphism on morphine- and fentanyl-mediated modulation of Ca²⁺ channels in humanized mouse sensory neurons
- 2011
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Ingår i: Anesthesiology. - : Lippincott Williams & Wilkins. - 0003-3022 .- 1528-1175. ; 115:5, s. 1054-1062
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele.METHODS: The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele.RESULTS: The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice.CONCLUSIONS: This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids.
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| 16. |
- Ruggeri, Barbara, et al.
(författare)
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Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis
- 2015
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 172:6, s. 543-552
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. Method: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents. Results: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task. Conclusions: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.
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| 17. |
- Ruggeri, Barbara, et al.
(författare)
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Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents
- 2018
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Ingår i: Journal of Child Psychology and Psychiatry. - : Wiley. - 0021-9630 .- 1469-7610. ; 9:6, s. 50-658
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Nociceptin is a key regulator linking environmental stress and alcohol drinking. In a genome-wide methylation analysis, we recently identified an association of a methylated region in the OPRL1 gene with alcohol-use disorders.METHODS: Here, we investigate the biological basis of this observation by analysing psychosocial stressors, methylation of the OPRL1 gene, brain response during reward anticipation and alcohol drinking in 660 fourteen-year-old adolescents of the IMAGEN study. We validate our findings in marchigian sardinian (msP) alcohol-preferring rats that are genetically selected for increased alcohol drinking and stress sensitivity.RESULTS: We found that low methylation levels in intron 1 of OPRL1 are associated with higher psychosocial stress and higher frequency of binge drinking, an effect mediated by OPRL1 methylation. In individuals with low methylation of OPRL1, frequency of binge drinking is associated with stronger BOLD response in the ventral striatum during reward anticipation. In msP rats, we found that stress results in increased alcohol intake and decreased methylation of OPRL1 in the nucleus accumbens.CONCLUSIONS: Our findings describe an epigenetic mechanism that helps to explain how psychosocial stress influences risky alcohol consumption and reward processing, thus contributing to the elucidation of biological mechanisms underlying risk for substance abuse.
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| 18. |
- Selim, Mohamed Kotb, et al.
(författare)
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Repetitive deep TMS in alcohol dependent patients halts progression of white matter changes in early abstinence
- 2023
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Ingår i: Psychiatry and Clinical Neurosciences. - : WILEY. - 1323-1316 .- 1440-1819.
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Alcohol use disorder (AUD) is the most prevalent form of addiction, with a great burden on society and limited treatment options. A recent clinical trial reported significant clinical benefits of deep transcranial magnetic stimulations (Deep TMS) targeting midline frontocortical areas. However, the underlying biological substrate remained elusive. Here, we report the effect of Deep TMS on the microstructure of white matter.Methods: A total of 37 (14 females) AUD treatment-seeking patients were randomized to sham or active Deep TMS. Twenty (six females) age-matched healthy controls were included. White matter integrity was evaluated by fractional anisotropy (FA). Secondary measures included brain functional connectivity and self-reports of craving and drinking units in the 3 months of follow-up period.Results: White matter integrity was compromised in patients with AUD relative to healthy controls, as reflected by the widespread reduction in FA. This alteration progressed during early abstinence (3 weeks) in the absence of Deep TMS. However, stimulation of midline frontocortical areas arrested the progression of FA changes in association with decreased craving and relapse scores. Reconstruction of axonal tracts from white-matter regions showing preserved FA values identified cortical regions in the posterior cingulate and dorsomedial prefrontal cortices where functional connectivity was persistently modulated. These effects were absent in the sham-stimulated group.Conclusions: By integrating brain structure and function to characterize the alcohol-dependent brain, this study provides mechanistic insights into the TMS effect, pointing to myelin plasticity as a possible mediator.
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| 19. |
- Solmi, Marco, et al.
(författare)
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Physical and mental health impact of COVID-19 on children, adolescents, and their families :
- 2022
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Ingår i: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 299, s. 367-376
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Tidskriftsartikel (refereegranskat)abstract
- Background: The COVID-19 pandemic has altered daily routines and family functioning, led to closing schools, and dramatically limited social interactions worldwide. Measuring its impact on mental health of vulnerable children and adolescents is crucial. Methods: The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT - www. coh-fit.com) is an on-line anonymous survey, available in 30 languages, involving >230 investigators from 49 countries supported by national/international professional associations. COH-FIT has thee waves (until the pandemic is declared over by the WHO, and 6-18 months plus 24-36 months after its end). In addition to adults, COH-FIT also includes adolescents (age 14-17 years), and children (age 6-13 years), recruited via nonprobability/snowball and representative sampling and assessed via self-rating and parental rating. Nonmodifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to promote health and prevent mental and physical illness in children and adolescents will be generated by COH-FIT. Co primary outcomes are changes in well-being (WHO-5) and a composite psychopathology P-Score. Multiple behavioral, family, coping strategy and service utilization factors are also assessed, including functioning and quality of life. Results: Up to June 2021, over 13,000 children and adolescents from 59 countries have participated in the COHFIT project, with representative samples from eleven countries. Limitations: Cross-sectional and anonymous design. Conclusions: Evidence generated by COH-FIT will provide an international estimate of the COVID-19 effect on childrens, adolescents and families, mental and physical health, well-being, functioning and quality of life, informing the formulation of present and future evidence-based interventions and policies to minimize adverse effects of the present and future pandemics on youth.
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| 20. |
- Solmi, Marco, et al.
(författare)
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The collaborative outcomes study on health and functioning during infection times in adults (COH-FIT-Adults) : Design and methods of an international online survey targeting physical and mental health effects of the COVID-19 pandemic
- 2022
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Ingår i: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 299, s. 393-407
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Tidskriftsartikel (refereegranskat)abstract
- Background: . High-quality comprehensive data on short-/long-term physical/mental health effects of the COVID-19 pandemic are needed. Methods: . The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is an international, multi-language (n=30) project involving >230 investigators from 49 countries/territories/regions, endorsed by national/international professional associations. COH-FIT is a multi-wave, on-line anonymous, cross-sectional survey [wave 1: 04/2020 until the end of the pandemic, 12 months waves 2/3 starting 6/24 months threreafter] for adults, adolescents (14-17), and children (6-13), utilizing non-probability/snowball and representative sampling. COH-FIT aims to identify non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to improve social/health outcomes in the general population/vulnerable subgrous during/after COVID-19. In adults, co-primary outcomes are change from pre-COVID-19 to intra-COVID-19 in well-being (WHO-5) and a composite psychopathology P-Score. Key secondary outcomes are a P-extended score, global mental and physical health. Secondary outcomes include health-service utilization/ functioning, treatment adherence, functioning, symptoms/behaviors/emotions, substance use, violence, among others. Results: . Starting 04/26/2020, up to 14/07/2021 >151,000 people from 155 countries/territories/regions and six continents have participated. Representative samples of >= 1,000 adults have been collected in 15 countries. Overall, 43.0% had prior physical disorders, 16.3% had prior mental disorders, 26.5% were health care workers, 8.2% were aged >= 65 years, 19.3% were exposed to someone infected with COVID-19, 76.1% had been in quarantine, and 2.1% had been COVID 19-positive. Limitations: . Cross-sectional survey, preponderance of non-representative participants. Conclusions: . Results from COH-FIT will comprehensively quantify the impact of COVID-19, seeking to identify high-risk groups in need for acute and long-term intervention, and inform evidence-based health policies/strategies during this/future pandemics.
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| 21. |
- Solmi, Marco, et al.
(författare)
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Validation of the Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) questionnaire for adults
- 2023
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Ingår i: Journal of Affective Disorders. - : ELSEVIER. - 0165-0327 .- 1573-2517. ; 326, s. 249-261
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the in-ternal validity of the co-primary outcome, a composite psychopathology "P-score". Methods: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r >= 0.5 with validated companion question-naires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed. Results: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (omega = 0.95). Factor structure was consistent across age and sex. Conclusions: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health.
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| 22. |
- Sommer, Wolfgang H., et al.
(författare)
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From a systems view to spotting a hidden island: A narrative review implicating insula function in alcoholism
- 2022
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Ingår i: Neuropharmacology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0028-3908 .- 1873-7064. ; 209
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Tidskriftsartikel (refereegranskat)abstract
- Excessive use of alcohol promotes the development of alcohol addiction, but the understanding of how alcohol induced brain alterations lead to addiction remains limited. To further this understanding, we adopted an unbiased discovery strategy based on the principles of systems medicine. We used functional magnetic resonance imaging data from patients and animal models of alcohol addiction-like behaviors, and developed mathematical models of the relapse-prone network states to identify brain sites and functional networks that can be selectively targeted by therapeutic interventions. Our systems level, non-local, and largely unbiased analyses converged on a few well-defined brain regions, with the insula emerging as one of the most consistent findings across studies. In proof-of-concept experiments we were able to demonstrate that it is possible to guide network dynamics towards increased resilience in animals but an initial translation into a clinical trial targeting the insula failed. Here, in a narrative review, we summarize the key experiments, methodological developments and knowledge gained from this complete round of a discovery cycle moving from identification of relapse-prone network states in humans and animals to target validation and intervention trial. Future concerted efforts are necessary to gain a deeper understanding of insula function a in a state-dependent, circuit-specific and cell population perspective, and to develop the means for insula-directed interventions, before therapeutic targeting of this structure may become possible.
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| 23. |
- Sreedharan, Smitha, et al.
(författare)
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GPR162 is expressed in the hypothalamus and is involved in food intake related behaviour
- 2011
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The Rhodopsin family of G protein-coupled receptors (GPCRs) includes about 270 non-olfactory receptors and is the largest family of GPCRs. About sixty non-olfactory Rhodopsin GPCRs are still orphans without known ligands, and fairly little is known about their functions. In this study, we present molecular, neuroanatomical, genetic and behavioral data implicating a Rhodopsin family protein, GPR162, in the regulation of food intake-related behaviour and glucose homeostasis. The real-time PCR data show that GPR162 is predominantly expressed in the CNS. The in situ hybridization results confirmed significant expression of GPR162 in several hypothalamic sites, amygdala, substantia nigra and ventral tegmental area, among others regions. In line with the distribution of the GPR162 mRNA in the feeding circuitry, antisense oligo knockdown of GPR162 caused a significant reduction in food intake but no effect was observed towards reduction in body weight in rats. Our human genetics studies suggest that genetic variants of GPR162 affect glucose homeostasis. In conclusion, this study provides evidence linking the orphan GPR162 gene with the regulation of food intake-related behaviour.
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| 24. |
- Sreedharan, Smitha, et al.
(författare)
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The G protein coupled receptor Gpr153 shares common evolutionary origin with Gpr162 and is highly expressed in central regions including the thalamus, cerebellum and the arcuate nucleus
- 2011
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 278:24, s. 4881-4894
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Tidskriftsartikel (refereegranskat)abstract
- The Rhodopsin family of G protein-coupled receptors (GPCRs) includes the phylogenetic α-group consisting of about 100 human members. The α-group is the only group of GPCRs that has many receptors for biogenic amines which are major drug targets. Several members of this group are orphan receptors and their functions are elusive. In this study we present a detailed phylogenetic and anatomical characterization of the Gpr153 receptor and also attempted to study its functional role. We identified the homologue of GPR153 in the elephant shark genome and phylogenetic and synteny analyses revealed that Gpr162 originated from Gpr153, through a duplication event before the radiation of the amphibian lineage. Quantitative real time PCR study reveals wide spread expression of GPR153 in the CNS and all the peripheral tissues investigated. Detailed in situ hybridization on mouse brain showed specifically high expression in the thalamus, cerebellum and the arcuate nucleus. The antisense oligodeoxynucleotide knockdown of GPR153 caused a slight reduction in food intake and the elevated plus maze test showed significant reduction in the percentage of time spent in the centre square, which points towards a probable role in decision making. This report provides the first detailed characterization of the evolution, expression and as well as primary functional properties of the GPR153 gene.
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| 25. |
- Taqi, Malik Mumtaz, 1983-
(författare)
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Mechanisms of Prodynorphin Gene Dysregulation in the Brain of Human Alcoholics
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The endogenous opioid system (EOS) including dynorphin opioid peptides and κ-opioid receptor (KOR) plays a critical role in alcohol dependence. Aims of the thesis were to evaluate whether the EOS undergoes molecular adaptations in brain areas involved in cognitive control of addiction in human alcohol dependent subjects, and to analyze the impact of genetic and epigenetic factors on these adaptive changes. The main findings were that (1) the dynorphin/KOR system including PDYN mRNA and dynorphins in the dorsolateral prefrontal cortex (dl-PFC), dynorphins in the hippocampus, and KOR mRNA in the orbitofrontal cortex (OFC), is upregulated in human alcoholics. No other significant changes in the EOS were found. (2) Three PDYN single nucleotide polymorphisms (SNPs), which show the most significant association with alcohol dependence, form CpG sites that are methylated in human brain at different levels. Methylation of the C, non-risk variant of the 3’-untranslated region (3’-UTR) SNP (rs2235749; C>T) was increased in dl-PFC and positively correlated with dynorphins. The DNA-binding factor that differentially targeted the T, risk allele and methylated and unmethylated C allele of this SNP was identified in human brain. We hypothesize that influences of the genetic, epigenetic and environmental factors may be integrated through alterations in methylation of the PDYN 3’jUTR CpG/SNP and, as a consequence, affect PDYN transcription and vulnerability to develop alcohol dependence. (3) The principal component analysis suggested that PDYN expression in the dl-PFC may be related to alcoholism, while in the hippocampus may depend on the genotype of the PDYN promoter SNP (rs1997794; T>C). The T, low risk allele of this SNP resides within non-canonical AP-1-binding element and may be targeted by JUND and FOSB proteins, the dominant AP-1 constituents in the human brain. The T to C transition abrogated AP-1 binding. The impact of genetic variations on PDYN transcription may be relevant for diverse adaptive responses of this gene to alcohol. (4) It was proposed that PDYN transcription may be regulated by intragenic DNA regulatory elements controlling the DNA-protein interactions through formation of non-canonical DNA secondary structures. The dynorphin-encoding sequence in PDYN was found to have potential to form such DNA structure in vitro, and this formation was affected by CpG methylation in this region. This methylation sensitive non-canonical DNA structure formation may be involved in regulation of initiation of PDYN transcription from alternative start sites located within this region, or in splicing of non-canonical mRNA. In conclusion, the dynorphin/KOR system has been identified as the site of robust adaptive changes associated with alcohol dependence in the areas of human brain involved in cognitive control of addiction. Regulation of PDYN was found to be brain area specific, apparently affected by the genetic and epigenetic factors, and possibly dependent on the internal properties of the gene such as its ability to form non-canonical DNA secondary structures.
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