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159. The Importance of Animals in Advancing Alcohol Use Disorder Research

Author

Helms, Christa M., Bell, Richard L., Bennett, Allyson J., Davies, Daryl L., Chester, Julia A., Kosten, Therese A., Leeman, Robert F., Panicker, Sangeeta, Platt, Donna M., Weiner, Jeff L., and Edwards, Scott

Subjects
Disease Models, Animal, Research, Animals, Alcohol-Related Disorders, Article
Published
2015

160. Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents

Author

Harris, R. Adron, primary, Bajo, Michal, additional, Bell, Richard L., additional, Blednov, Yuri A., additional, Varodayan, Florence P., additional, Truitt, Jay M., additional, de Guglielmo, Giordano, additional, Lasek, Amy W., additional, Logrip, Marian L., additional, Vendruscolo, Leandro F., additional, Roberts, Amanda J., additional, Roberts, Edward, additional, George, Olivier, additional, Mayfield, Jody, additional, Billiar, Timothy R., additional, Hackam, David J., additional, Mayfield, R. Dayne, additional, Koob, George F., additional, Roberto, Marisa, additional, and Homanics, Gregg E., additional

Published
2016
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165. CIS-Acting Allele-Specific Expression Differences Induced by Alcohol and Impacted by Sex as Well as Parental Genotype of Origin.

Author

Chiao-Ling Lo, Lumeng, Lawrence, Bell, Richard L., Tiebing Liang, Lossie, Amy C., Muir, Williams M., and Zhou, Feng C.

Subjects
ALLELES, ANIMAL experimentation, ALCOHOL drinking, ETHANOL, EUTHANASIA, GENE expression, GENETIC polymorphisms, MEMBRANE proteins, NEURAL transmission, NEUROTRANSMITTERS, RATS, SEX distribution, GENE expression profiling, SEQUENCE analysis, EPIGENOMICS, GENOTYPES
Abstract

Background: Alcohol use disorders (AUDs) are influenced by complex interactions between the genetics of the individual and their environment. We have previously identified hundreds of polygenic genetic variants between the selectively bred high- and low-alcohol drinking (HAD and LAD) rat lines. Here, we report allele-specific expression (ASE) differences, between the HAD2 and LAD2 rat lines. Methods: The HAD2 and LAD2 rats, which have been sequenced, were reciprocally crossed to generate 10 litters of F1 progeny. For 5 of these litters, the sire was HAD2, and for the other 5 litters, the sire was a LAD2. From these 10 litters, 2 males and 2 females were picked from each F1 litter (N = 40 total). The F1 pups were divided, balancing for sex and direction of cross, into an alcohol (15%) versus a water control group. Alcohol drinking started in the middle of adolescence (~postnatal day 35) and lasted 9 weeks. At the end of these treatments, rats were euthanized, the nucleus accumbens was dissected, and RNA was processed for RNA-sequencing and ASE analyses. Results: Analyses revealed that adolescent ethanol (EtOH) drinking, individual EtOH drinking levels, parentage, and sex-of-animal affected ASEs of about 300 genes. The identified genes included those associated with EtOH metabolism (e.g., Aldh2); neuromodulatory function (e.g., Cckbr, Slc6a7, and Slc1a1); ion channel activity (e.g., Kcnc3); and other synaptic and epigenetic functions. Conclusions: These data indicate that EtOH drinking differentially amplified paternal versus maternal allelic contribution to the transcriptome. We hypothesize that this was due, at least in part, to EtOH-induced changes in cis-regulation of polymorphisms previously identified between the HAD2 and LAD2 rat lines. This report highlights the complexity of gene-by-environment interactions mediating a genetic predisposition for, and/or the active development of, AUDs. [ABSTRACT FROM AUTHOR]

Published
2018
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166. AZI23’UTR Is a New SLC6A3 Downregulator Associated with an Epistatic Protection Against Substance Use Disorders.

Author

Liu, Kefu, Yu, Jinlong, Zhao, Juan, Zhou, Yanhong, Xiong, Nian, Xu, Jie, Wang, Tao, Bell, Richard L., Qing, Hong, and Lin, Zhicheng

Abstract

Regulated activity of SLC6A3, which encodes the human dopamine transporter (DAT), contributes to diseases such as substance abuse disorders (SUDs); however, the exact transcription mechanism remains poorly understood. Here, we used a common genetic variant of the gene, intron 1 DNP1B sequence, as bait to screen and clone a new transcriptional activity, AZI23′UTR, for SLC6A3. AZI23′UTR is a 3′ untranslated region (3′UTR) of the human 5-Azacytidine Induced 2 gene (AZI2) but appeared to be transcribed independently of AZI2. Found to be present in both human cell nuclei and dopamine neurons, this RNA was shown to downregulate promoter activity through a variant-dependent mechanism in vitro. Both reduced RNA density ratio of AZI23′UTR/AZI2 and increased DAT mRNA levels were found in ethanol-naive alcohol-preferring rats. Secondary analysis of dbGaP GWAS datasets (Genome-Wide Association Studies based on the database of Genotypes and Phenotypes) revealed significant interactions between regions upstream of AZI23′UTR and SLC6A3 in SUDs. Jointly, our data suggest that AZI23′UTR confers variant-dependent transcriptional regulation of SLC6A3, a potential risk factor for SUDs. [ABSTRACT FROM AUTHOR]

Published
2018
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175. Ethanol and nicotine interaction within the posterior ventral tegmental area in male and female alcohol-preferring rats: evidence of synergy and differential gene activation in the nucleus accumbens shell

Author

Truitt, William A., primary, Hauser, Sheketha R., additional, Deehan, Gerald A., additional, Toalston, Jamie E., additional, Wilden, Jessica A., additional, Bell, Richard L., additional, McBride, William J., additional, and Rodd, Zachary A., additional

Published
2014
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176. Reinforcing Properties and Neurochemical Response of Ethanol within the Posterior Ventral Tegmental Area Are Enhanced in Adulthood by Periadolescent Ethanol Consumption

Author

Toalston, Jamie E., primary, Deehan, Gerald A., additional, Hauser, Sheketha R., additional, Engleman, Eric A., additional, Bell, Richard L., additional, Murphy, James M., additional, Truitt, William A., additional, McBride, William J., additional, and Rodd, Zachary A., additional

Published
2014
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180. ‘Gem’ Pear

Author

Bell, Richard L., primary, van der Zwet, Tom, additional, Castagnoli, Steve, additional, Einhorn, Todd, additional, Turner, Janet D., additional, Spotts, Robert, additional, Moulton, Gary A., additional, Reighard, Greg L., additional, and Shane, William W., additional

Published
2014
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182. Genetical genomic determinants of alcohol consumption in rats and humans

Author

Tabakoff, Boris, Tabakoff, Boris, Saba, Laura, Printz, Morton, Flodman, Pam, Hodgkinson, Colin, Goldman, David, Koob, George, Richardson, Heather N, Kechris, Katerina, Bell, Richard L, Hubner, Norbert, Heinig, Matthias, Pravenec, Michal, Mangion, Jonathan, Legault, Lucie, Dongier, Maurice, Conigrave, Katherine M, Whitfield, John B, Saunders, John, Grant, Bridget, Hoffman, Paula L, Tabakoff, Boris, Tabakoff, Boris, Saba, Laura, Printz, Morton, Flodman, Pam, Hodgkinson, Colin, Goldman, David, Koob, George, Richardson, Heather N, Kechris, Katerina, Bell, Richard L, Hubner, Norbert, Heinig, Matthias, Pravenec, Michal, Mangion, Jonathan, Legault, Lucie, Dongier, Maurice, Conigrave, Katherine M, Whitfield, John B, Saunders, John, Grant, Bridget, and Hoffman, Paula L

Abstract

BackgroundWe have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs). Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human animal models of alcohol drinking behavior, could inform interpretation of genetic association studies with human populations.ResultsIn the HXB/BXH recombinant inbred (RI) rats, correlation analysis of brain gene expression levels with alcohol consumption in a two-bottle choice paradigm, and filtering based on behavioral and gene expression quantitative trait locus (QTL) analyses, generated a list of candidate genes. A literature-based, functional analysis of the interactions of the products of these candidate genes defined pathways linked to presynaptic GABA release, activation of dopamine neurons, and postsynaptic GABA receptor trafficking, in brain regions including the hypothalamus, ventral tegmentum and amygdala. The analysis also implicated energy metabolism and caloric intake control as potential influences on alcohol consumption by the recombinant inbred rats. In the human populations, polymorphisms in genes associated with GABA synthesis and GABA receptors, as well as genes related to dopaminergic transmission, were associated with alcohol consumption.ConclusionOur results emphasize the importance of the signaling pathways identified using the non-human animal models, rather than single gene products, in identifying factors responsible for complex traits such as alcohol consumption. The results suggest cross-species similarities in pathways that influence predisposition to consume alcohol by rats and humans. The im

Published
2009

191. Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats.

Author

McClintick, Jeanette N., McBride, William J., Bell, Richard L., Ding, Zheng‐Ming, Liu, Yunlong, Xuei, Xiaoling, and Edenberg, Howard J.

Subjects
CHOLESTEROL metabolism, RNA analysis, ACETYLCHOLINE, ADOLESCENCE, ANIMAL experimentation, ANXIETY, ASPARTIC acid, BIOLOGICAL models, BRAIN stem, CALCIUM, CELL receptors, ETHANOL, FEAR, GABA, GENE expression, GLUTAMIC acid, GLYCINE, NEUROPEPTIDES, NEUROTRANSMITTERS, POTASSIUM, RATS, RESEARCH funding, SEROTONIN, SODIUM, BINGE drinking, DESCRIPTIVE statistics, SEQUENCE analysis, MEMBRANE transport proteins
Abstract

Background Binge drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including increased pain, fear, and anxiety. The periaqueductal gray ( PAG) is involved in processing pain, fear, and anxiety. The effects of adolescent binge drinking on gene expression in this region have yet to be studied. Methods Male adolescent alcohol-preferring (P) rats were exposed to repeated binge drinking (three 1-hour sessions/d during the dark/cycle, 5 days/wk for 3 weeks starting at 28 days of age; ethanol intakes of 2.5 to 3 g/kg/session). We used RNA sequencing to assess the effects of ethanol intake on gene expression. Results Ethanol significantly altered the expression of 1,670 of the 12,123 detected genes: 877 (53%) decreased. In the glutamate system, 23 genes were found to be altered, including reduction in 7 of 10 genes for metabotropic and NMDA receptors. Subunit changes in the NMDA receptor may make it less sensitive to ethanol. Changes in GABAA genes would most likely increase the ability of the PAG to produce tonic inhibition. Five serotonin receptor genes, 6 acetylcholine receptor genes, and 4 glycine receptor genes showed decreased expression in the alcohol-drinking rats. Opioid genes (e.g., Oprk1, Oprm1) and genes for neuropeptides linked to anxiety and panic behaviors (e.g., Npy1r) had mostly decreased expression. Genes for 27 potassium, 10 sodium, and 5 calcium ion channels were found to be differentially expressed. Nine genes in the cholesterol synthesis pathway had decreased expression, including Hmgcr, encoding the rate-limiting enzyme. Genes involved in the production of myelin also had decreased expression. Conclusions The results demonstrate that binge alcohol drinking during adolescence produces developmental changes in the expression of key genes within the PAG; many of these changes point to increased susceptibility to pain, fear, and anxiety, which could contribute to excessive drinking to relieve these negative effects. [ABSTRACT FROM AUTHOR]

Published
2016
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196. Reduced Levels of mGlu2 Receptors within the Prelimbic Cortex Are Not Associated with Elevated Glutamate Transmission or High Alcohol Drinking

Author

Ding, Zheng‐Ming, Ingraham, Cynthia M., Hauser, Sheketha R., Lasek, Amy W., Bell, Richard L., and McBride, William J.

Abstract

A Grm2 cys407* stop codon mutation, which results in a loss of the metabotropic glutamate 2 (mGlu2) receptor protein, was identified as being associated with high alcohol drinking by alcohol‐preferring (P) rats. The objectives of the current study were to characterize the effects of reduced levels of mGlu2 receptors on glutamate transmission and alcohol drinking. Quantitative no‐net‐flux microdialysis was used to test the hypothesis that basal extracellular glutamate levels in the prelimbic (PL) cortex and nucleus accumbens shell (NACsh) will be higher in P than Wistar rats. A lentiviral‐delivered short‐hairpin RNA (shRNA)‐mediated knockdown was used to test the hypothesis that reduced levels of mGlu2 receptors within the PL cortex will increase voluntary alcohol drinking by Wistar rats. A linear regression analysis was used to test the hypothesis that there will be a significant correlation between the Grm2 cys407* mutation and level of alcohol intake. Extracellular glutamate concentrations within the PL cortex (3.6 ± 0.6 vs. 6.4 ± 0.6 μM) and NACsh (3.2 ± 0.4 vs. 6.6 ± 0.6 μM) were significantly lower in female P than female Wistar rats. Western blot detected the presence of mGlu2 receptors in these regions of female Wistar rats, but not female P rats. Micro‐infusion of shRNAs into the PL cortex significantly reduced local mGlu2 receptor levels (by 40%), but did not alter voluntary alcohol drinking in male Wistar rats. In addition, there was no significant correlation between the Grm2 mutation and alcohol intake in 36 rodent lines (r= 0.29, p> 0.05). Collectively, these results suggest a lack of association between the loss of mGlu2 receptors and glutamate transmission in the NACsh and PL cortex of female P rats, and between the level of mGlu2 receptors in the PL cortex and alcohol drinking of male Wistar rats. A Grm2cys407* stop codon mutation was identified in alcohol preferring (P) rats and certain Wistar rats with Hannover origin, and has been associated with high alcohol drinking (Wood et al. 2017, Zhou et al. 2013). This linear regression study examined potential relation between the Grm2cys407* allele frequency and alcohol drinking in 36 rodent lines, but did not find significant correlation (p > 0.05). The results suggest that Grm2genetic variation may not determine alcohol drinking.

Published
2017
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197. Negative Affect‐Associated USVAcoustic Characteristics Predict Future Excessive Alcohol Drinking and Alcohol Avoidance in Male P and NPRats

Author

Reno, James M., Thakore, Neha, Cormack, Lawrence K., Schallert, Timothy, Bell, Richard L., Maddox, W. Todd, and Duvauchelle, Christine L.

Abstract

Negative emotional status and adverse emotional events increase vulnerability to alcohol abuse. Ultrasonic vocalizations (USVs) emitted by rats are a well‐established model of emotional status that can reflect positive or negative affective responses in real time. Most USVstudies assess counts, yet each USVis a multidimensional data point characterized by several acoustic characteristics that may provide insight into the neurocircuitry underlying emotional response. USVs emitted from selectively bred alcohol‐naïve and alcohol‐experienced alcohol‐preferring and nonpreferring rats (P and NPrats) were recorded during 4‐hour sessions on alternating days over 4 weeks. Linear mixed modeling (LMM) and linear discriminant analysis (LDA) were applied to USVacoustic characteristics (e.g., frequency, duration, power, and bandwidth) of negative affect (22 to 28 kilohertz [kHz])‐ and positive (50 to 55 kHz) affect‐related USVs. Hundred percent separation between alcohol‐naïve P and NPrats was achieved through a linear combination (produced by LDA) of USVacoustic characteristics of 22‐ to 28‐kHz USVs, whereas poor separation (36.5%) was observed for 50‐ to 55‐kHz USVs. 22‐ to 28‐kHz LDAseparation was high (87%) between alcohol‐experienced P and NPrats, but was poor for 50‐ to 55‐kHz USVs (57.3%). USVmean frequency and duration were the highest weighted characteristics in both the naïve and experienced 22‐ to 28‐kHz LDArepresentations suggesting that alcohol experience does not alter the representations. LMManalyses of 22‐ to 28‐kHz USVacoustic characteristics matched the LDAresults. Poor LDAseparation was observed between alcohol‐naïve and alcohol‐experienced P rats for both 22‐ to 28‐kHz and 50‐ to 55‐kHz USVs. Advanced statistical analysis of negative affect‐associated USVdata predicts future behaviors of excessive alcohol drinking and alcohol avoidance in selectively bred rats. USVcharacteristics across rat lines reveal affect‐related motivation to consume alcohol and may predict neural pathways mediating emotional response. Further characterization of these differences could delineate particular neurocircuitry and methods to ameliorate dysregulated emotional states often observed in human alcohol abusers. Diagram depicts a mixed population of rats categorized into P and NP groups based solely on 22 kHz USV record data. The procedure includes USV recordings, analyses of the vocalization recordings using the WAAVES program (Reno et al. 2013) and tabulation of 22–28 kHz USV acoustic characteristics (mean frequency, duration, bandwidth and power). Categorization of P versus NP groups is based solely on a linear combination of acoustic characteristics.

Published
2017
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