Exaggerated impulsivity: a cause or a consequence of adolescent repeated ethanol withdrawal?

Binge alcohol drinking is a major public health concern world wide and its occurrence is rising among young adults. Using animal and human subjects, this thesis evaluates the impact of binge drinking during a time of neurodevelopment on aspects of impulse control, and studies the potential of addressing a molecular target, the μ-opioid receptor, to alleviate elevated impulsive-like behaviour. First, the nature of impulsivity is described in a review paper. We demonstrate the suitability of the Five-Choice Serial Reaction Time Task (5-CSRTT) for measuring one facet of impulsivity, waiting impulsivity, in mice. Bridging the animal and human laboratories, we developed a novel human analogue of the 5-CSRTT (paper 2). Elevated impulsive behaviour was detected in both young human binge drinkers and in an ethanol-preferring strain of mice, suggesting impulsivity to occur as a prelude to heavy alcohol use. In a second approach (paper 3), we studied the long term effects of intermittent alcohol exposure using a mouse model of adolescent binge drinking. We revealed disrupted impulsive behaviour in adulthood in two different inbred strains, which differ in baseline impulsivity and ethanol drinking patterns, indicating that impulsivity is also a consequence of ethanol exposure. In paper 4 we studied the ability of an opioid antagonist to improve top-down control of impulsive behaviour. Consilience between species and paradigms will need to be further addressed in future studies, but antagonising μ-opioid systems may aid in preventing binge drinking by facilitating inhibitory control mechanisms. Collectively, from animal and human evidence, this thesis will argue that exaggerated impulsivity may result from repeated ethanol withdrawal in adolescence as well as being a pre-existing endophenotype contributing to adolescent binge drinking. Disentangling such a relationship may help delineate new lines of intervention for at-risk individuals

Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse.

Alcohol use disorder (AUD) is defined by several symptom criteria, which can be dissected further at the genetic level. Over the past several years, our understanding of the genetic factors influencing alcohol use and abuse has progressed tremendously; numerous loci have been implicated in different aspects of alcohol use. Previously known associations with alcohol-metabolizing enzymes (ADH1B, ALDH2) have been replicated definitively. In addition, novel associations with loci containing the genes KLB, GCKR, CRHR1, and CADM2 have been reported. Downstream analyses have leveraged these genetic findings to reveal important relationships between alcohol use behaviors and both physical and mental health. AUD and aspects of alcohol misuse have been shown to overlap strongly with psychiatric disorders, whereas aspects of alcohol consumption have shown stronger links to metabolism. These results demonstrate that the genetic architecture of alcohol consumption only partially overlaps with the genetics of clinically defined AUD. We discuss the limitations of using quantitative measures of alcohol use as proxy measures for AUD, and we outline how future studies will require careful phenotype harmonization to properly capture the genetic liability to AUD

Heightened impulsivity: associated with family history of alcohol misuse, and a consequence of alcohol intake

BACKGROUND Youths with family history (FH) of alcoholism are at greater risk of developing alcohol use disorder (AUD); heightened impulsive behavior may underlie such increased vulnerability. Here, we studied waiting impulsivity (previously suggested to predispose to alcohol drinking) in young moderate-to-heavy social drinkers (18 to 33 years old) characterized as family history positive (FHP) and negative (FHN) following an alcoholic or nonalcoholic (placebo) drink. METHODS Two groups of young male and female social drinkers (n = 64) were administered an acute dose of alcohol (0.8 g/kg) or placebo. One group (FHP; n = 24) had first-degree relatives with problems of alcohol misuse; the other group (FHN) did not. Participants completed 4 variants of the Sx-5CSRTT, a task measuring waiting impulsivity. In addition, other types of impulsive behavior were tested (by means of the stop-signal task [SST]; information sampling task [IST]; Delay Discounting Questionnaire; 2-choice impulsivity paradigm; and time estimation task). RESULTS Young FHP adults showed more premature responding than FHN when evaluated under increased attentional load (high waiting impulsivity), while, in contrast, they presented a more conservative strategy on the IST (less impulsive behavior), compared to FHN. Acute alcohol impaired inhibitory control on the SST in all participants, and induced a marginal increase of premature responses, but did not affect other measures of impulsivity. CONCLUSIONS Assessing for exaggerated waiting impulsivity may provide a potential endophenotype associated with risk for the development of alcohol addiction (i.e., offspring of alcoholics)

Mouse and human genetic analyses associate kalirin with ventral striatal activation during impulsivity and with alcohol misuse

Impulsivity is associated with a spectrum of psychiatric disorders including drug addiction. To investigate genetic associations with impulsivity and initiation of drug taking, we took a two-step approach. First, we identified genes whose expression level in prefrontal cortex, striatum and accumbens were associated with impulsive behaviour in the 5-choice serial reaction time task across 10 BXD recombinant inbred (BXD RI) mouse strains and their progenitor C57BL/6J and DBA2/J strains. Behavioural data were correlated with regional gene expression using GeneNetwork (www.genenetwork.org), to identify 44 genes whose probability of association with impulsivity exceeded a false discovery rate of <0.05. We then interrogated the IMAGEN database of 1423 adolescents for potential associations of SNPs in human homologues of those genes identified in the mouse study, with brain activation during impulsive performance in the Monetary Incentive Delay task, and with novelty seeking scores from the Temperament and Character Inventory, as well as alcohol experience. There was a significant overall association between the human homologues of impulsivity-related genes and percentage of premature responses in the MID task and with fMRI BOLD-response in ventral striatum (VS) during reward anticipation. In contrast, no significant association was found between the polygenic scores and anterior cingulate cortex activation. Univariate association analyses revealed that the G allele (major) of the intronic SNP rs6438839 in the KALRN gene was significantly associated with increased VS activation. Additionally, the A-allele (minor) of KALRN intronic SNP rs4634050, belonging to the same haplotype block, was associated with increased frequency of binge drinking

Evaluation of delay discounting as a transdiagnostic research domain criteria indicator in 1388 general community adults

Background The Research Domain Criteria (RDoC) approach proposes a novel psychiatric nosology using transdiagnostic dimensional mechanistic constructs. One candidate RDoC indicator is delay discounting (DD), a behavioral economic measure of impulsivity, based predominantly on studies examining DD and individual conditions. The current study sought to evaluate the transdiagnostic significance of DD in relation to several psychiatric conditions concurrently. Methods Participants were 1388 community adults (18–65) who completed an in-person assessment, including measures of DD, substance use, depression, anxiety, posttraumatic stress disorder, and attention-deficit hyperactivity disorder (ADHD). Relations between DD and psychopathology were examined with three strategies: first, examining differences by individual condition using clinical cut-offs; second, examining DD in relation to latent psychopathology variables via principal components analysis (PCA); and third, examining DD and all psychopathology simultaneously via structural equation modeling (SEM). Results Individual analyses revealed elevations in DD were present in participants screening positive for multiple substance use disorders (tobacco, cannabis, and drug use disorder), ADHD, major depressive disorder (MDD), and an anxiety disorder (ps < 0.05–0.001). The PCA produced two latent components (substance involvement v. the other mental health indicators) and DD was significantly associated with both (ps < 0.001). In the SEM, unique significant positive associations were observed between the DD latent variable and tobacco, cannabis, and MDD (ps < 0.05–0.001). Conclusions These results provide some support for DD as a transdiagnostic indicator, but also suggest that studies of individual syndromes may include confounding via comorbidities. Further systematic investigation of DD as an RDoC indicator is warranted

Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise

The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene exprssion by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging

Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates

Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise

The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging

Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids \u27not as prescribed\u27. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (

Long-term exercise modulates hippocampal gene expression in sencescent females mice

Altres ajuts: FI-DGR 2011 de la Generalitat de CatalunyaThe senescence-accelerated SAMP8 mouse is considered a useful non-transgenic model for studying aspects of progressive cognitive decline and Alzheimer's disease (AD). Using SAMR1 mice as controls, here we explored the effects of 6 months of voluntary wheel running in 10-month-old female SAMP8 mice. Exercise in SAMP8 mice improved phenotypic features associated with premature aging (i.e., skin color and body tremor) and enhanced vascularization and BDNF gene expression in the hippocampus compared with controls. With the aim of identifying genes involved in brain aging responsive to long-term exercise, we performed whole genome microarray studies in hippocampus from sedentary SAMP8 (P8sed), SAMR1 (R1sed), and exercised SAMP8 (P8run) mice. The genes differentially expressed in P8sed versus R1sed were considered as putative aging markers (i) and those differentially expressed in P8run versus P8sed were considered as genes modulated by exercise (ii). Genes differentially expressed in both comparisons (i and ii) were considered as putative aging genes responsive to physical exercise. We identified 34 genes which met both criteria. Gene ontology analysis revealed that they are mainly involved in functions related to extracellular matrix maintenance. Selected genes were validated by real-time quantitative PCR assays, i.e., collagen type 1 alpha 1 (col1a1), collagen type 1 alpha 2 (col1a2), fibromodulin (fmod), prostaglandin D(2) synthase (ptgds), and aldehyde dehydrogenase (Aldh1a2). As a whole, our study suggests that exercise training during adulthood may prevent or delay gene expression alterations and processes associated with hippocampal aging in at-risk subjects