Evidence for a Long-Lasting Compulsive Alcohol Seeking Phenotype in Rats

Excessive drinking to intoxication is the major behavioral characteristic of those addicted to alcohol but it is not the only one. Indeed, individuals addicted to alcohol also crave alcoholic beverages and spend time and put much effort into compulsively seeking alcohol, before eventually drinking large amounts. Unlike this excessive drinking, for which treatments exist, compulsive alcohol seeking is therefore another key feature of the persistence of alcohol addiction since it leads to relapse and for which there are few effective treatments. Here we provide novel evidence for the existence in rats of an individual vulnerability to switch from controlled to compulsive, punishment-resistant alcohol seeking. Alcohol-preferring rats given access to alcohol under an intermittent 2-bottle choice procedure to establish their alcohol-preferring phenotype were subsequently trained instrumentally to seek and take alcohol on a chained schedule of reinforcement. When stable seeking-taking performance had been established, completion of cycles of seeking responses resulted unpredictably either in punishment (0.45 mA foot-shock) or the opportunity to make a taking response for access to alcohol. Compulsive alcohol seeking, maintained in the face of the risk of punishment, emerged in only a subset of rats with a predisposition to prefer and drink alcohol, and was maintained for almost a year. We show further that a selective and potent μ-opioid receptor antagonist (GSK1521498) reduced both alcohol seeking and alcohol intake in compulsive and non-compulsive rats, indicating its therapeutic potential to promote abstinence and prevent relapse in individuals addicted to alcohol.The present study was funded by a Medical Research Council Programme Grant (no. G1002231) and by GlaxoSmithKline (GSK), which has a commercial interest in GSK1521498. The production of the P rats was funded by the R24 Alcohol Research Resource Award grant (R24 AA015512) from NIAAA

Alteration of gene expression by alcohol exposure at early neurulation

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated that alcohol exposure at early neurulation induces growth retardation, neural tube abnormalities, and alteration of DNA methylation. To explore the global gene expression changes which may underline these developmental defects, microarray analyses were performed in a whole embryo mouse culture model that allows control over alcohol and embryonic variables.</p> <p>Result</p> <p>Alcohol caused teratogenesis in brain, heart, forelimb, and optic vesicle; a subset of the embryos also showed cranial neural tube defects. In microarray analysis (accession number GSM9545), adopting hypothesis-driven Gene Set Enrichment Analysis (GSEA) informatics and intersection analysis of two independent experiments, we found that there was a collective reduction in expression of neural specification genes (neurogenin, <it>Sox5, Bhlhe22</it>), neural growth factor genes [<it>Igf1, Efemp1</it>, <it>Klf10 </it>(<it>Tieg), and Edil3</it>], and alteration of genes involved in cell growth, apoptosis, histone variants, eye and heart development. There was also a reduction of retinol binding protein 1 (<it>Rbp1</it>), and <it>de novo </it>expression of aldehyde dehydrogenase 1B1 (<it>Aldh1B1</it>). Remarkably, four key hematopoiesis genes (glycophorin A, adducin 2, beta-2 microglobulin, and ceruloplasmin) were absent after alcohol treatment, and histone variant genes were reduced. The down-regulation of the neurospecification and the neurotrophic genes were further confirmed by quantitative RT-PCR. Furthermore, the gene expression profile demonstrated distinct subgroups which corresponded with two distinct alcohol-related neural tube phenotypes: an open (ALC-NTO) and a closed neural tube (ALC-NTC). Further, the epidermal growth factor signaling pathway and histone variants were specifically altered in ALC-NTO, and a greater number of neurotrophic/growth factor genes were down-regulated in the ALC-NTO than in the ALC-NTC embryos.</p> <p>Conclusion</p> <p>This study revealed a set of genes vulnerable to alcohol exposure and genes that were associated with neural tube defects during early neurulation.</p

Does Lack of Multinutrient Supplementation During Early Pregnancy Increase Vulnerability to Alcohol-Related Preterm or Small-for-Gestational-Age Births?

The objective of this study was to assess whether women who do not take multinutrient supplements during early pregnancy are more susceptible to the effects of low-to-moderate alcohol consumption on preterm birth and small-for-gestational-age birth (SGA) compared to women who do take multinutrients. This analysis included 800 singleton live births to mothers from a cohort of pregnant women recruited for a population-based cohort study conducted in the Kaiser Permanente Medical Care Program in Northern California. Participants were recruited in their first trimester of pregnancy and information about their alcohol use and supplement intake during pregnancy was collected. Preterm birth (n = 53, 7%) was defined as a delivery prior to 37 completed weeks of gestation and SGA birth (n = 124, 16%) was defined as birth weight less than the 10th percentile for the infant’s gestational age and sex compared to US singleton live births. A twofold increase in the odds of SGA birth attributed to low-to-moderate alcohol intake was found among multinutrient supplement non-users (95% CI: 1.1, 5.3). Yet, among multinutrient supplement users, there was no increased risk of an SGA birth for women who drank low-to-moderately compared to women who abstained (aOR: 0.97, 95% CI: 0.6, 1.6). Similar results emerged for preterm birth. Our findings provide marginal evidence that multinutrient supplementation during early pregnancy may modify the risk of SGA births and preterm birth associated with alcohol consumption during pregnancy and may have important implications for pregnant women and women of child-bearing age. However, future research needs to be conducted

Differential Proteomic Analysis of Mammalian Tissues Using SILAM

Differential expression of proteins between tissues underlies organ-specific functions. Under certain pathological conditions, this may also lead to tissue vulnerability. Furthermore, post-translational modifications exist between different cell types and pathological conditions. We employed SILAM (Stable Isotope Labeling in Mammals) combined with mass spectrometry to quantify the proteome between mammalian tissues. Using 15N labeled rat tissue, we quantified 3742 phosphorylated peptides in nuclear extracts from liver and brain tissue. Analysis of the phosphorylation sites revealed tissue specific kinase motifs. Although these tissues are quite different in their composition and function, more than 500 protein identifications were common to both tissues. Specifically, we identified an up-regulation in the brain of the phosphoprotein, ZFHX1B, in which a genetic deletion causes the neurological disorder Mowat–Wilson syndrome. Finally, pathway analysis revealed distinct nuclear pathways enriched in each tissue. Our findings provide a valuable resource as a starting point for further understanding of tissue specific gene regulation and demonstrate SILAM as a useful strategy for the differential proteomic analysis of mammalian tissues

Regulation of Motor Function and Behavior by Atypical Chemokine Receptor 1

The final publication is available at Springer via http://dx.doi.org/10.1007/s10519-014-9665-7Atypical Chemokine Receptor 1 (ACKR1), previously known as the Duffy Antigen Receptor for Chemokines, stands out among chemokine receptors for its high selective expression on Purkinje cells of the cerebellum, consistent with the ability of ACKR1 ligands to activate Purkinje cells in vitro. Nevertheless, evidence for ACKR1 regulation of brain function in vivo has been lacking. Here we demonstrate that Ackr1−/− mice have markedly impaired balance and ataxia when placed on a rotating rod and increased tremor when injected with harmaline, a drug that induces whole-body tremor by activating Purkinje cells. Ackr1−/− mice also exhibited impaired exploratory behavior, increased anxiety-like behavior and frequent episodes of marked hypoactivity under low-stress conditions. The behavioral phenotype of Ackr1−/− mice was the opposite of the phenotype occurring in mice with cerebellar degeneration and the defects persisted when Ackr1 was deficient only on non-hematopoietic cells. We conclude that normal motor function and behavior depend in part on negative regulation of Purkinje cell activity by Ackr1

Prenatal exposure to cigarette smoke or alcohol and cerebellum volume in attention-deficit/hyperactivity disorder and typical development

Prenatal exposure to teratogenic substances, such as nicotine or alcohol, increases the risk of developing attention-deficit/hyperactivity disorder (ADHD). To date, studies examining this relationship have used symptom scales as outcome measures to assess the effect of prenatal exposure, and have not investigated the neurobiological pathways involved. This study explores the effect of prenatal exposure to cigarettes or alcohol on brain volume in children with ADHD and typically developing controls. Children with ADHD who had been exposed prenatally to either substance were individually matched to children with and without ADHD who had not been. Controls who had been exposed prenatally were also individually matched to controls who had not been. For prenatal exposure to both smoking and alcohol, we found a pattern where subjects with ADHD who had been exposed had the smallest brain volumes and unexposed controls had the largest, with intermediate volumes for unexposed subjects with ADHD. This effect was most pronounced for cerebellum. A similar reduction fell short of significance for controls who had been exposed to cigarettes, but not alcohol. Our results are consistent with an additive effect of prenatal exposure and ADHD on brain volume, with the effects most pronounced for cerebellum