scholarly journals Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder

2020 ◽  
Vol 14 ◽  
Author(s):  
Caroline E. Strong ◽  
Mohamed Kabbaj
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Treatment Options ◽  
Dorsal Striatum ◽  
Brain Regions ◽  
Repeated Treatment ◽  
Therapeutic Effects ◽  
Acute Administration ◽  
Treatment Regimens ◽  
Antidepressant Effects

Alcohol use disorder (AUD) is the most prevalent substance use disorder and causes a significant global burden. Relapse rates remain incredibly high after decades of attempting to develop novel treatment options that have failed to produce increased rates of sobriety. Ketamine has emerged as a potential treatment for AUD following its success as a therapeutic agent for depression, demonstrated by several preclinical studies showing that acute administration reduced alcohol intake in rodents. As such, ketamine’s therapeutic effects for AUD are now being investigated in clinical trials with the hope of it being efficacious in prolonging sobriety from alcohol in humans (ClinicalTrials.gov, Identifier: NCT01558063). Importantly, ketamine’s antidepressant effects only last for about 1-week and because AUD is a lifelong disorder, repeated treatment regimens would be necessary to maintain sobriety. This raises questions regarding its safety for AUD treatment since ketamine itself has the potential for addiction. Therefore, this review aims to summarize the neuroadaptations related to alcohol’s addictive properties as well as ketamine’s therapeutic and addictive properties. To do this, the focus will be on reward-related brain regions such as the nucleus accumbens (NAc), dorsal striatum, prefrontal cortex (PFC), hippocampus, and ventral tegmental area (VTA) to understand how acute vs. chronic exposure will alter reward signaling over time. Additionally, evidence from these studies will be summarized in both male and female subjects. Accordingly, this review aims to address the safety of repeated ketamine infusions for the treatment of AUD. Although more work about the safety of ketamine to treat AUD is warranted, we hope this review sheds light on some answers about the safety of repeated ketamine infusions.

scholarly journals Nalmefene attenuates neural alcohol cue-reactivity in the ventral striatum and subjective alcohol craving in patients with alcohol use disorder

2021 ◽  
Author(s):  
Damian Karl ◽  
J. Malte Bumb ◽  
Patrick Bach ◽  
Christina Dinter ◽  
Anne Koopmann ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Ventral Striatum ◽  
Neuronal Response ◽  
Cue Reactivity ◽  
Treatment Options ◽  
A Priori ◽  
Dorsal Striatum ◽  
Region Of Interest ◽  
Double Blind

Abstract Rationale Alcohol use disorder is a common and devastating mental illness for which satisfactory treatments are still lacking. Nalmefene, as an opioid receptor modulator, could pharmacologically support the reduction of drinking by reducing the (anticipated) rewarding effects of alcohol and expanding the range of treatment options. It has been hypothesized that nalmefene acts via an indirect modulation of the mesolimbic reward system. So far, only a few imaging findings on the neuronal response to nalmefene are available. Objectives We tested the effect of a single dose of 18 mg nalmefene on neuronal cue-reactivity in the ventral and dorsal striatum and subjective craving. Methods Eighteen non-treatment-seeking participants with alcohol use disorder (67% male, M = 50.3 ± 13.9 years) with a current high-risk drinking level (M = 76.9 ± 52 g of pure alcohol per day) were investigated using a cue-reactivity task during functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled, cross-over study/design. In addition, self-reported craving was assessed before and after exposure to alcohol cues. Results An a priori defined region of interest (ROI) analysis of fMRI data from 15 participants revealed that nalmefene reduced alcohol cue-reactivity in the ventral, but not the dorsal striatum. Additionally, the subjective craving was significantly reduced after the cue-reactivity task under nalmefene compared to placebo. Conclusion In the present study, reduced craving and cue-reactivity to alcohol stimuli in the ventral striatum by nalmefene indicates a potential anti-craving effect of this drug via attenuation of neural alcohol cue-reactivity.

scholarly journals Alcohol use disorder causes global changes in splicing in the human brain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Derek Van Booven ◽  
Mengying Li ◽  
J. Sunil Rao ◽  
Ilya O. Blokhin ◽  
R. Dayne Mayfield ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Human Brain ◽  
Alcohol Use Disorder ◽  
Brain Regions ◽  
Gene Set Enrichment Analysis ◽  
Splicing Factor ◽  
Central Nucleus ◽  
Global Changes ◽  
Aberrant Expression ◽  
Altered Expression

AbstractAlcohol use disorder (AUD) is a widespread disease leading to the deterioration of cognitive and other functions. Mechanisms by which alcohol affects the brain are not fully elucidated. Splicing constitutes a nuclear process of RNA maturation, which results in the formation of the transcriptome. We tested the hypothesis as to whether AUD impairs splicing in the superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). To evaluate splicing, bam files from STAR alignments were indexed with samtools for use by rMATS software. Computational analysis of affected pathways was performed using Gene Ontology Consortium, Gene Set Enrichment Analysis, and LncRNA Ontology databases. Surprisingly, AUD was associated with limited changes in the transcriptome: expression of 23 genes was altered in SFC, 14 in NA, 102 in BLA, and 57 in CNA. However, strikingly, mis-splicing in AUD was profound: 1421 mis-splicing events were detected in SFC, 394 in NA, 1317 in BLA, and 469 in CNA. To determine the mechanism of mis-splicing, we analyzed the elements of the spliceosome: small nuclear RNAs (snRNAs) and splicing factors. While snRNAs were not affected by alcohol, expression of splicing factor heat shock protein family A (Hsp70) member 6 (HSPA6) was drastically increased in SFC, BLA, and CNA. Also, AUD was accompanied by aberrant expression of long noncoding RNAs (lncRNAs) related to splicing. In summary, alcohol is associated with genome-wide changes in splicing in multiple human brain regions, likely due to dysregulation of splicing factor(s) and/or altered expression of splicing-related lncRNAs.

scholarly journals Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial

2021 ◽  
Author(s):  
James C. Garbutt ◽  
Alexei B. Kampov-Polevoy ◽  
Cort Pedersen ◽  
Melissa Stansbury ◽  
Robyn Jordan ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Controlled Trial ◽  
Treatment Options ◽  
Double Blind ◽  
Randomized Controlled ◽  
Main Effect ◽  
Dsm Iv ◽  
Drop Outs ◽  
Positive Effect

AbstractIdentification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABAB agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90 mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd = 10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112) = 4.16, p = 0.018, d = 0.51 95%CI (0.06–0.95), 13.6 fewer HDD) and %ABST (F(2,112) = 3.68, p = 0.028, d = 0.49 95%CI (0.04–0.93), 12.9 more abstinent days)] and was driven by the 90 mg/day dose. A sex × dose interaction effect was present for both %HDD (F(2,110) = 5.48, p = 0.005) and %ABST (F(2,110) = 3.19, p = 0.045). Men showed a marginally positive effect for 90 mg/day compared to PBO (%HDD t(110) = 1.88, p = 0.063, d = 0.36 95%CI (−0.09–0.80), 15.8 fewer HDD days; %ABST t(110) = 1.68 (p = 0.096, d = 0.32 95%CI (−0.12–0.76), 15.7 more ABST)) with no effect for 30 mg/day. Women showed a positive effect for 30 mg/day (%HDD, t(110) = 3.19, p = 0.002, d = 0.61 95%CI (0.16–1.05), 26.3 fewer HDD days; %ABST t(110) = 2.73, p = 0.007, d = 0.52 95%CI (0.07–0.96), 25.4 more ABST days) with marginal effects for 90 mg/day on %ABST (p = 0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90 mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.

scholarly journals Family history of alcohol use disorder is associated with brain structural and functional changes in healthy first-degree relatives

2019 ◽  
Vol 62 ◽  
pp. 107-115 ◽  
Author(s):  
Irina Filippi ◽  
Nicolas Hoertel ◽  
Eric Artiges ◽  
Guillaume Airagnes ◽  
Christophe Guérin-Langlois ◽  
...  
Keyword(s):  
Family History ◽  
Alcohol Use ◽  
Childhood Maltreatment ◽  
Alcohol Use Disorder ◽  
Grey Matter ◽  
Brain Regions ◽  
Whole Brain ◽  
Childhood Trauma Questionnaire ◽  
Functional Changes ◽  
History Of

Abstract Background: Neuroimaging studies of vulnerability to Alcohol Use Disorder (AUD) have identified structural and functional variations which might reflect inheritable features in alcohol-naïve relatives of AUD individuals (FH+) compared to controls having no such family history (FH-). However, prior research did not simultaneously account for childhood maltreatment, any clinically significant disorder and maternal AUD. Therefore, we mainly aimed to investigate the brain structure and reward-related neural activations (fMRI), using whole-brain analysis in FH+ young adults with no prevalent confounders. Methods: 46 FH+ and 45 FH- male and female participants had no severe childhood maltreatment exposure, neither any psychiatric disorder or AUD, nor a prenatal exposure to maternal AUD. We used a 3 T MRI coupled with a whole brain voxel-based method to compare between groups the grey matter volumes and activations in response to big versus small wins during a Monetary Incentive Delay task. The Childhood Trauma Questionnaire score was used as confounding variable in the analyses to account for the remaining variance between groups. Results: Compared to FH- controls, FH+ participants had smaller grey matter volumes in the frontal and cingulate regions as well as in the bilateral nucleus accumbens and right insula. The FH+ participants’ fMRI datasets denoted a blunted activation in the middle cingulum with respect to FH- controls’ during the processing of reward magnitude, and a greater activation in the anterior cingulum in response to anticipation of a small win. Conclusions: Family history of alcohol use disorder is linked to structural and functional variations including brain regions involved in reward processes.

A multi‐omic analysis of the dorsal striatum in an animal model of divergent genetic risk for alcohol use disorder

2020 ◽  
Author(s):  
Gregory G. Grecco ◽  
David L. Haggerty ◽  
Emma H. Doud ◽  
Brandon M. Fritz ◽  
Fuqin Yin ◽  
...  
Keyword(s):  
Animal Model ◽  
Alcohol Use ◽  
Genetic Risk ◽  
Alcohol Use Disorder ◽  
Dorsal Striatum

The Association Between Impulsivity and Relapse in Patients With Alcohol Use Disorder: A Literature Review

2020 ◽  
Author(s):  
Wilco Sliedrecht ◽  
Hendrik G Roozen ◽  
Katie Witkiewitz ◽  
Ranne de Waart ◽  
Geert Dom
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Treatment Options ◽  
Careful Consideration ◽  
Self Report ◽  
Future Research ◽  
Impulsive Choice ◽  
Cognitive Behavioural ◽  
Trait Impulsivity ◽  
Future Work

Abstract Aim Impulsivity has been identified as a key relapse risk factor in patients with alcohol use disorder (AUD); however, the inherent characteristics of this relationship have been largely understudied. The heterogeneity of AUD and variation in impulsivity constructs require careful consideration to inform future work examining the relationship. This study sought to review empirical findings examining facets of impulsivity and AUD relapse. Methods A systematic search strategy was employed to capture studies on impulsivity measures related to AUD relapse. Impulsivity measures were qualitatively organized in terms of ‘trait impulsivity’—typically measured by self-report questionnaires—and ‘behavioural impulsivity’, i.e. ‘motor impulsivity’, ‘impulsive choice’ and ‘reflection impulsivity, assessed with cognitive–behavioural tasks. Results Seventeen peer-reviewed papers were identified. Relapse outcomes varied substantially in relation to impulsivity measures. Twelve papers included aspects of ‘trait impulsivity’, and nine studies included ‘behavioural impulsivity’ measures, from which five studies dealt with the ‘impulsive choice’ subcategory. The Barratt Impulsivity Scale was the self-report questionnaire that was most frequently used. Conclusions All three included facets of impulsivity (‘trait-, motor- and impulsive choice impulsivity’) were associated with AUD relapse, but none seemed to be superior to another. This study confirmed that research on the relation between impulsivity and AUD relapse is relatively scarce. Future research and treatment options are proposed.

Frontostriatal Connectivity During Reward Anticipation

2017 ◽  
Vol 225 (3) ◽  
pp. 232-243 ◽  
Author(s):  
Alena Becker ◽  
Martin Fungisai Gerchen ◽  
Martina Kirsch ◽  
Bettina Ubl ◽  
Sivaniya Subramaniapillai ◽  
...  
Keyword(s):  
At Risk ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Ventral Striatum ◽  
Dorsal Striatum ◽  
Reward Processing ◽  
Reward Anticipation ◽  
Patient Groups ◽  
The Common ◽  
Related Pattern

Abstract. Neurobiological research indicates that altered reward processing is among the most promising risk mechanisms in alcohol use disorder and depression. To elucidate differences and similarities between both disorders, we investigated clinical patients and at-risk individuals in two studies using a functional magnetic resonance imaging (fMRI) monetary reward paradigm. In the first study, alcohol use disorder patients compared to depressed and healthy individuals showed increased activation of the ventral striatum during reward anticipation. In contrast, both patient groups showed reduced frontostriatal connectivity compared to controls. In the second study, at-risk comorbid individuals showed decreased activation in the dorsal striatum along with decreased frontostriatal connectivity. While the connectivity results replicate the common pattern found for the patient groups, the activation results indicate a more depression-related pattern in individuals prone to developing both disorders. In conclusion, frontostriatal connectivity might be a promising transdiagnostic marker for depression, alcohol use disorder, and their comorbidity.

scholarly journals Effects of cortisol administration on craving during in vivo exposure in patients with alcohol use disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Leila M. Soravia ◽  
Franz Moggi ◽  
Dominique J.-F. de Quervain
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Underlying Mechanism ◽  
Double Blind ◽  
Extinction Memory ◽  
Exposure Sessions ◽  
Novel Treatment Strategies

AbstractAlcohol-associated memories and craving play a crucial role in the development and maintenance of alcohol use disorder (AUD). As treatment options are limited in AUD, novel treatment strategies focus on the manipulation of alcohol-associated memories. The stress hormone cortisol affects various memory processes, and first clinical studies have shown that it inhibits the retrieval of disorder-specific memories and enhances extinction memory. This study aimed to investigate the effects of a single oral administration of cortisol on craving in patients with AUD during repeated in vivo exposure to alcohol pictures and the preferred alcoholic drink. In a double-blind, block-randomized, placebo-controlled cross-over design, 46 patients with AUD were treated with two sessions of in vivo exposure to alcohol. Cortisol (20 mg) or placebo was orally administered 1 h before each test day. Craving, stress, and cortisol were repeatedly measured during exposure sessions. Results show, that cortisol administration had distinct effects on craving depending on the severity of AUD and test day. While cortisol administration significantly enhanced craving during exposure on the first test day in patients with less severe AUD, it reduced craving in patients with more severe AUD. Independent of the cortisol administration, repeated in vivo exposure reduced craving from test day 1 to test day 2. In conclusion, adding cortisol to in vivo exposure might be a promising approach for reducing the strength of alcohol-associated memories and might promote the consolidation of extinction memory in patients with severe AUD. However, the differential effect of cortisol on craving depending on AUD severity cannot be conclusively explained and highlights the need for future studies elucidating the underlying mechanism.

scholarly journals Epigenome-wide Association Study of Alcohol Use Disorder in Five Brain Regions

2021 ◽  
Author(s):  
Lea Zillich ◽  
Josef Frank ◽  
Fabian Streit ◽  
Marion M Friske ◽  
Jerome C Foo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Use ◽  
Brain Region ◽  
Alcohol Use Disorder ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Human Brain Tissue ◽  
Postmortem Human Brain ◽  
Association Analyses ◽  
Cpg Sites

Alcohol Use Disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n=53) and controls (n=58) using a brain region-specific approach. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted Correlation Network Analysis (WGCNA), gene-set and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < .05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < .05) were found in the CN (n=6), VS (n=18) and ACC (n=1). These findings were mapped to several genes including IREB2, SLC30A8, and DDAH2. In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD

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