A neural substrate of compulsive alcohol use.
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ABSTRACT:
SUBMITTER: Domi E
PROVIDER: S-EPMC8373126 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ethanol inhibits the proliferation of neural stem cells in the fetal, adolescent, and adult brain. The consequences are cognitive deficits associated with fetal alcohol spectrum disorder and alcohol use disorder. We tested the hypothesis that ethanol affects progression through cell cycle checkpoints by differentially modifying transcriptional processes. Monolayer cultures of NS-5 neural stem cells were treated for 48 hr with the mitogenic agent FGF2 or the anti-mitogenic TGFβ1 in the absence or presence of ethanol. Cell cycle elongation was induced by a global down-regulation of genes involved in cell cycle progression, including the cyclin E system. Checkpoint regulation occurred downstream of p21 and Jun-oncogene signaling cascades. Thus, ethanol can affect cell cycle progression by altering transcript expression of strategic genes downstream of the G1/S checkpoint. NS5 neural stem cells were grown in Euromed Media supplemented with N2 and glutamine. Cells were plated on poly-ornathine and laminin in the presence of FGF2 (10 ng/ul) and EGF (10 ng/ul) for 24 hrs. Media was removed, cells were rinsed, and placed in growth factor free conditions for 4 hrs. NS5 cells were then exposed to one of four treatment for 48 hrs: FGF2 (10 ng/ul) only, FGF2 (10 ng/ul) and ethanol (400 mg/dl), TGF-beta1 (10 ng/ul) only, or TGF-beta1 (10 ng/ul) and ethanol (400 mg/dl). Total RNA was collected immediately following treatment.
2010-04-12 | E-GEOD-19436 | biostudies-arrayexpress
Project description:Ethanol inhibits the proliferation of neural stem cells in the fetal, adolescent, and adult brain. The consequences are cognitive deficits associated with fetal alcohol spectrum disorder and alcohol use disorder. We tested the hypothesis that ethanol affects progression through cell cycle checkpoints by differentially modifying transcriptional processes. Monolayer cultures of NS-5 neural stem cells were treated for 48 hr with the mitogenic agent FGF2 or the anti-mitogenic TGFβ1 in the absence or presence of ethanol. Cell cycle elongation was induced by a global down-regulation of genes involved in cell cycle progression, including the cyclin E system. Checkpoint regulation occurred downstream of p21 and Jun-oncogene signaling cascades. Thus, ethanol can affect cell cycle progression by altering transcript expression of strategic genes downstream of the G1/S checkpoint.
2010-04-01 | GSE19436 | GEO
Project description:ObjectiveUnderage drinking is widely recognized as a leading public health and social problem for adolescents in the United States. Being able to identify at-risk adolescents before they initiate heavy alcohol use could have important clinical and public health implications; however, few investigations have explored individual-level precursors of adolescent substance use. This prospective investigation used machine learning with demographic, neurocognitive, and neuroimaging data in substance-naive adolescents to identify predictors of alcohol use initiation by age 18.MethodParticipants (N=137) were healthy substance-naive adolescents (ages 12-14) who underwent neuropsychological testing and structural and functional magnetic resonance imaging (sMRI and fMRI), and then were followed annually. By age 18, 70 youths (51%) initiated moderate to heavy alcohol use, and 67 remained nonusers. Random forest classification models identified the most important predictors of alcohol use from a large set of demographic, neuropsychological, sMRI, and fMRI variables.ResultsRandom forest models identified 34 predictors contributing to alcohol use by age 18, including several demographic and behavioral factors (being male, higher socioeconomic status, early dating, more externalizing behaviors, positive alcohol expectancies), worse executive functioning, and thinner cortices and less brain activation in diffusely distributed regions of the brain.ConclusionsIncorporating a mix of demographic, behavioral, neuropsychological, and neuroimaging data may be the best strategy for identifying youths at risk for initiating alcohol use during adolescence. The identified risk factors will be useful for alcohol prevention efforts and in research to address brain mechanisms that may contribute to early drinking.
| S-EPMC5288131 | biostudies-literature
Project description:Background Though compulsive drinking is a hallmark of alcohol use disorder (AUD), little is known of the neural mechanisms driving this behavior. To further the understanding of the neural underpinnings of this compulsivity, a meta-analytic approach was used to examine gray matter (GM) volume differences related to AUD, and contrast these differences with GM volume differences in obsessive-compulsive disorder (OCD), to find common underlying regional brain differences. Methods We systematically meta-analyzed case-control studies investigating GM volume that used whole-brain voxel-based morphometry separately for AUD and OCD and then directly compared the results of both. Seed-based d Mapping software was used to perform the meta-analyses. Results The AUD meta-analysis used 19 citations, with 736 individuals with AUD and 827 control individuals. The OCD meta-analysis had 25 citations, with 995 individuals with OCD and 1177 control individuals. The AUD group showed decreased GM in areas including frontal, limbic, temporal, and cerebellar regions. The OCD group had decreased GM in frontal and insular regions but increases in the hypothalamus and brainstem. Importantly, the main outcome showed that both groups had decreased GM overlapping in the anterior cingulate cortex and insula. Brain regions were p < .05 corrected. Conclusions Common brain regional differences in the anterior cingulate cortex and insula that overlap between AUD and OCD suggest that interventions targeting these regions could prove to be beneficial in treating compulsive drinking related to AUD. Further research into the functional role of these brain regions in the etiology of compulsive drinking in AUD is warranted.
| S-EPMC9616258 | biostudies-literature
Project description:RationaleBrain iron accumulation has been observed in neuropsychiatric disorders and shown to be related to neurodegeneration.ObjectivesIn this study, we used quantitative susceptibility mapping (QSM), an emerging MRI technique developed for quantifying tissue magnetic susceptibility, to examine brain iron accumulation in individuals with alcohol use disorder (AUD) and its relation to compulsive drinking.MethodsBased on our previous projects, QSM was performed as a secondary analysis with gradient echo sequence images, in 186 individuals with AUD and 274 healthy participants. Whole-brain susceptibility values were calculated with morphology-enabled dipole inversion and referenced to the cerebrospinal fluid. Then, the susceptibility maps were compared between AUD individuals and healthy participants. The relationship between drinking patterns and susceptibility was explored.ResultsWhole-brain analyses showed that the susceptibility in the dorsal striatum (putamen and caudate) among AUD individuals was higher than healthy participants and was positively related to the Obsessive Compulsive Drinking Scale (OCDS) scores and the amount of drinking in the past three months.ConclusionsIncreased susceptibility suggests higher iron accumulation in the dorsal striatum in AUD. This surrogate for the brain iron level was linearly associated with the compulsive drinking pattern and the recent amount of drinking, which provides us a new clinical perspective in relation to brain iron accumulation, and also might indicate an association of AUD with neuroinflammation as a consequence of brain iron accumulation. The iron accumulation in the striatum is further relevant for functional imaging studies in AUD by potentially producing signal dropout and artefacts in fMRI images.
| S-EPMC9879829 | biostudies-literature
Project description:BACKGROUND:Alcohol use is commonly initiated during adolescence, with earlier onset known to increase the risk for alcohol use disorder (AUD). Altered function in neural reward circuitry is thought to increase the risk for AUD. To test the hypothesis that adolescent alcohol misuse primes the brain for alcohol-related psychopathology in early adulthood, we examined whether adolescent alcohol consumption rates predicted reward responsivity in the ventral striatum (VS), and in turn, AUD symptoms in adulthood. METHODS:A total of 139 low income, racially diverse urban males reported on their alcohol use at ages 11, 12, 15, and 17; completed self-reports of personality, psychiatric interviews, and a functional magnetic resonance imaging (fMRI) scan at age 20; and completed a psychiatric interview at age 22. We measured adolescent alcohol use trajectories using latent growth curve modeling and measured neural responses to monetary reward using a VS region of interest. We tested indirect effects of adolescent alcohol use on AUD symptoms at age 22 via VS reward-related reactivity at age 20. RESULTS:Greater acceleration in adolescent alcohol use predicted increased VS response during reward anticipation at age 20. VS reactivity to reward anticipation at age 20 predicted AUD symptoms at age 22, over and above concurrent symptoms. Accelerated adolescent alcohol use predicted AUD symptoms in early adulthood via greater VS reactivity to reward anticipation. CONCLUSIONS:Prospective findings support a pathway through which adolescent alcohol use increases the risk for AUD in early adulthood by impacting reward-related neural functioning. These results highlight increased VS reward-related reactivity as a biomarker for AUD vulnerability.
| S-EPMC7066874 | biostudies-literature
Project description:RATIONALE:Compared to the general population, adult Attention-Deficit / Hyperactivity Disorder (ADHD) is more prevalent in patients with Alcohol Use Disorder (AUD). Impaired behavioral inhibition is a common characteristic in both ADHD and AUD. Relapse risk is increased in patients with AUD and comorbid, untreated ADHD and in AUD patients with increased neural cue-reactivity. OBJECTIVES:In this study, we examined the interaction between neural correlates of behavioral inhibition and alcohol cue-reactivity with a hybrid imaging task. METHODS:Out of 69 adult study participants, we included n?=?49 in our final analyses: Individuals had a diagnosis of either AUD (n?=?13), ADHD (n?=?14) or both (n?=?5), or were healthy controls (HC; n?=?17). The functional magnetic resonance imaging paradigm aimed to examine the combined effects of both an interference-inhibition task ("Simon-task") and an alcohol cue-reactivity task. Instead of segregating by diagnostic group, we pursued a dimensional approach in which we compared measures of AUD and ADHD severity, as well as the interaction of both, using multiple regression analyses. RESULTS:The four groups did not differ on the behavioral level on either the inhibition task or the alcohol cue-reactivity task. However, brain activation in frontal control and reward-related regions during completion of the combined tasks were related to ADHD and AUD severity (symptom load). During presentation of both alcohol cues and the inhibition task, participants with higher AUD and ADHD symptom load exhibited greater BOLD (blood oxygen level dependent) responses in subcortical reward-related regions. CONCLUSIONS:Our findings support the hypothesis that ADHD additionally diminishes inhibition ability in individuals with AUD. This may increase relapse risk when confronted with alcohol cues. Further, it is crucial for patients with comorbid AUD and ADHD to take into account not only reduced cognitive control over behavioral inhibition but also simultaneously heightened alcohol cue-reactivity.
| S-EPMC7239811 | biostudies-literature
Project description:Addiction to cocaine is commonly preceded by experiences with legal or decriminalized drugs, such as alcohol, nicotine, and marijuana. The biological mechanisms by which these gateway drugs contribute to cocaine addiction are only beginning to be understood. We report that in the rat, prior alcohol consumption results in enhanced addiction-like behavior to cocaine, including continued cocaine use despite aversive consequences. Conversely, prior cocaine use has no effect on alcohol preference. Long-term, but not short-term, alcohol consumption promotes proteasome-mediated degradation of the nuclear histone deacetylases HDAC4 and HDAC5 in the nucleus accumbens, a brain region critical for reward-based memory. Decreased nuclear HDAC activity results in global H3 acetylation, creating a permissive environment for cocaine-induced gene expression. We also find that selective degradation of HDAC4 and HDAC5, facilitated by the class II-specific HDAC inhibitor MC1568, enhances compulsive cocaine self-administration. These results parallel our previously reported findings that the gateway drug nicotine enhances the behavioral effects of cocaine via HDAC inhibition. Together, our findings suggest a shared mechanism of action for the gateway drugs alcohol and nicotine, and reveal a novel mechanism by which environmental factors may alter the epigenetic landscape of the reward system to increase vulnerability to cocaine addiction.
| S-EPMC5665598 | biostudies-literature
Project description:RationaleAlcohol 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.ObjectivesWe tested the effect of a single dose of 18 mg nalmefene on neuronal cue-reactivity in the ventral and dorsal striatum and subjective craving.MethodsEighteen 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.ResultsAn 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.ConclusionIn 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.
| S-EPMC8292278 | biostudies-literature
Project description:RationaleThe co-occurrence of alcohol consumption and sexual activity is associated with increased risk for sexual assault, sexually transmitted disease, and unplanned pregnancy among young adult women with alcohol use disorder (AUD). There is considerable previous work demonstrating neural reactivity to alcohol cues in AUD. Because alcohol consumption and sexual behavior are both rewarding and tend to co-occur, sexual cues may produce similar neural reactivity in women with AUD, possibly indicating a shared mechanism underlying reactivity to both types of cues. Alternatively, reactivity to alcohol versus sexual cues may be distinct, suggesting domain-specific mechanisms.ObjectivesWe investigated whether the decision vulnerabilities in AUD women regarding sexual activity were related to differences in brain activation compared to control women.MethodsWomen with (n = 15) and without (n = 16) AUD completed a hypothetical decision-making task during fMRI that presented low- or high-risk scenarios involving visual sexual, appetitive, and neutral cues.ResultsResults showed that sexual cues were more often endorsed by women with AUD compared to controls and elicited differential brain activation patterns in frontal, visual, and reward regions. During high-risk decisions, women with AUD failed to downregulate activation, causing hyperactivation compared to controls.ConclusionsVisual sexual cues produced reactivity like that previously demonstrated for alcohol cues, suggesting a shared or domain-general mechanism for alcohol and sexual cue reactivity in women with AUD. Riskier sexual decisions in women with AUD may be a consequence of repeatedly pairing alcohol use and sexual activity, a characteristic behavior of this population.
| S-EPMC8238910 | biostudies-literature