Quantitative trait loci contributing to physiological and behavioural ethanol responses after acute and chronic treatment.

The aim of the present study was the identification of gene loci that contribute to the development and manifestation of behaviours related to acute and chronic alcohol exposure, as well as to alcohol withdrawal. For this purpose, we performed a serial behavioural phenotyping of 534 animals from the second filial (F2) generation of a C57BL/6J and C3H/HeJ mice intercross in paradigms with relevance to alcohol dependence. First, ethanol-induced hypothermia was determined in ethanol-naive animals. The mice then received an ethanol solution for several weeks as their only fluid source. Ethanol tolerance, locomotor activity and anxiety-related behaviours were evaluated. The ethanol was next withdrawn and the withdrawal severity was assessed. The ethanol-experienced animals were finally analysed in a two-bottle choice paradigm to determine ethanol preference and stress-induced changes in ethanol preference. The genotypes of these mice were subsequently assessed by microsatellite marker mapping. We genotyped 264 markers with an average marker distance of 5.56 cM, which represents a high-density whole genome coverage. Quantitative trait loci (QTL) were subsequently identified using univariate analysis performed with the R/qtl tool, which is an extensible, interactive environment for mapping QTL in experimental crosses. We found QTL that have already been published, thus validating the serial phenotyping protocol, and identified several novel loci. Our analysis demonstrates that the various responses to ethanol are regulated by independent groups of genes.

[1]  S. Cichon,et al.  The Opioid Peptides Enkephalin and β-Endorphin in Alcohol Dependence , 2008, Biological Psychiatry.

[2]  D. Nicole Riherd,et al.  Ethanol potentiates dopamine uptake and increases cell surface distribution of dopamine transporters expressed in SK-N-SH and HEK-293 cells. , 2008, Alcohol.

[3]  K. Buck,et al.  Molecular analyses and identification of promising candidate genes for loci on mouse chromosome 1 affecting alcohol physical dependence and associated withdrawal , 2008, Genes, brain, and behavior.

[4]  J. Hofstetter,et al.  Mapping a locus for alcohol physical dependence and associated withdrawal to a 1.1 Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2‐23.3 , 2008, Genes, brain, and behavior.

[5]  M. Schuckit,et al.  Genetic factors influencing alcohol dependence , 2008, British journal of pharmacology.

[6]  R. Beninger,et al.  Dopaminergic mechanism of reward-related incentive learning: Focus on the dopamine d3 receptor , 2008, Neurotoxicity Research.

[7]  R. Radcliffe,et al.  Short-term selection for acute ethanol tolerance and sensitization from an F2 population derived from the high and low alcohol-sensitive selectively bred rat lines. , 2007, Alcohol.

[8]  A. C. Hansson,et al.  Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress , 2006, Proceedings of the National Academy of Sciences.

[9]  N. Grahame,et al.  Candidate genes and their regulatory elements: alcohol preference and tolerance , 2006, Mammalian Genome.

[10]  Jonathan Flint,et al.  The genetic basis of emotional behaviour in mice , 2006, European Journal of Human Genetics.

[11]  A. Boyle,et al.  Genetic basis for the psychostimulant effects of nicotine: a quantitative trait locus analysis in AcB/BcA recombinant congenic mice , 2005, Genes, brain, and behavior.

[12]  P. Sokoloff,et al.  The dopamine D3 receptor and drug dependence: Effects on reward or beyond? , 2005, Neuropharmacology.

[13]  L. Ray,et al.  Alcoholism: the dissection for endophenotypes , 2005, Dialogues in clinical neuroscience.

[14]  J. Crabbe,et al.  The syntaxin binding protein 1 gene (Stxbp1) is a candidate for an ethanol preference drinking locus on mouse chromosome 2. , 2005, Alcoholism, clinical and experimental research.

[15]  K. Gill,et al.  Genetic analysis of alcohol intake in recombinant inbred and congenic strains derived from A/J and C57BL/6J progenitors , 2005, Mammalian Genome.

[16]  Paul M. Jenkins,et al.  Genetic correlation between the free-choice oral consumption of nicotine and alcohol in C57BL/6J × C3H/HeJ F2 intercross mice , 2005, Behavioural Brain Research.

[17]  Rajita Sinha,et al.  Stress enhancement of craving during sobriety: a risk for relapse. , 2005, Alcoholism, clinical and experimental research.

[18]  Annie E. Hill,et al.  Mapping Quantitative Trait Loci for Anxiety in Chromosome Substitution Strains of Mice , 2005, Genetics.

[19]  C. Harrington,et al.  On the integration of alcohol-related quantitative trait loci and gene expression analyses. , 2004, Alcoholism, clinical and experimental research.

[20]  J. Flint,et al.  QTL Analysis of Multiple Behavioral Measures of Anxiety in Mice , 2004, Behavior genetics.

[21]  Eric S. Lander,et al.  Genetic Dissection of Complex Traits with Chromosome Substitution Strains of Mice , 2004, Science.

[22]  J. Flint,et al.  Multivariate analysis of quantitative trait loci influencing variation in anxiety-related behavior in laboratory mice , 2004, Mammalian Genome.

[23]  M. Low,et al.  The mapping of quantitative trait loci underlying strain differences in locomotor activity between 129S6 and C57BL/6J mice , 2003, Mammalian Genome.

[24]  J. Crabbe,et al.  Chromosomal loci influencing chronic alcohol withdrawal severity , 2003, Mammalian Genome.

[25]  D. Dohrman,et al.  Ethanol modulates nicotine-induced upregulation of nAChRs , 2003, Brain Research.

[26]  B. Dudek,et al.  Genetic analysis of the psychomotor stimulant effect of ethanol , 2003, Genes, brain, and behavior.

[27]  G. Dawson,et al.  Genetic Mapping of Variation in Spatial Learning in the Mouse , 2003, The Journal of Neuroscience.

[28]  J. Drouin,et al.  Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency. , 2003, Genes & development.

[29]  M. Palkovits,et al.  A Critical Role for the Cannabinoid CB1 Receptors in Alcohol Dependence and Stress-Stimulated Ethanol Drinking , 2003, The Journal of Neuroscience.

[30]  R. Nussbaum,et al.  The development of a highly informative mouse Simple Sequence Length Polymorphism (SSLP) marker set and construction of a mouse family tree using parsimony analysis. , 2003, Genome research.

[31]  J. Flint,et al.  Multiple Cross Mapping (MCM) markedly improves the localization of a QTL for ethanol‐induced activation , 2002, Genes, brain, and behavior.

[32]  J. Sikela,et al.  Quantitative trait loci affecting initial sensitivity and acute functional tolerance to ethanol-induced ataxia and brain cAMP signaling in BXD recombinant inbred mice. , 2002, The Journal of pharmacology and experimental therapeutics.

[33]  F. Holsboer,et al.  Enhanced and Delayed Stress-Induced Alcohol Drinking in Mice Lacking Functional CRH1 Receptors , 2002, Science.

[34]  J. Crabbe,et al.  Mapping murine loci for physical dependence on ethanol , 2002, Psychopharmacology.

[35]  V. Bolivar,et al.  Mapping of quantitative trait loci with knockout/congenic strains. , 2001, Genome research.

[36]  Richard Paylor,et al.  The use of behavioral test batteries: Effects of training history , 2001, Physiology & Behavior.

[37]  J. Crabbe,et al.  Mapping genes that regulate density of dopamine transporters and correlated behaviors in recombinant inbred mice. , 2001, The Journal of pharmacology and experimental therapeutics.

[38]  R. Cohen,et al.  Quantitative trait loci affecting the behavior of A/J and CBA/J intercross mice in the elevated plus maze , 2001, Mammalian Genome.

[39]  A. Collins,et al.  Potential regulation of nicotine and ethanol actions by alpha4-containing nicotinic receptors. , 2001, Alcohol.

[40]  Jonathan Flint,et al.  QTL analysis identifies multiple behavioral dimensions in ethological tests of anxiety in laboratory mice , 2001, Current Biology.

[41]  G. Hanson,et al.  Methamphetamine decreases mouse striatal dopamine transporter activity: roles of hyperthermia and dopamine. , 2000, European journal of pharmacology.

[42]  R. Hitzemann,et al.  Effect of genetic cross on the detection of quantitative trait loci and a novel approach to mapping QTLs , 2000, Pharmacology Biochemistry and Behavior.

[43]  C. Vadász,et al.  Scanning of five chromosomes for alcohol consumption loci. , 2000, Alcohol.

[44]  Robert Hitzemann,et al.  Identification and Time Dependence of Quantitative Trait Loci for Basal Locomotor Activity in the BXD Recombinant Inbred Series and a B6D2 F2 Intercross , 2000, Behavior genetics.

[45]  C. Vadász,et al.  Mapping of quantitative trait loci for ethanol preference in quasi-congenic strains. , 2000, Alcohol.

[46]  J. Cole,et al.  Low alcohol preference among the ”high alcohol preference” C57 strain of mice; preference increased by saline injections , 1999, Psychopharmacology.

[47]  Jonathan Flint,et al.  High-resolution mapping of quantitative trait loci for emotionality in selected strains of mice , 1999, Mammalian Genome.

[48]  Robert Hitzemann,et al.  Identification of an Acute Ethanol Response Quantitative Trait Locus on Mouse Chromosome 2 , 1999, The Journal of Neuroscience.

[49]  K. Gill,et al.  Alcohol preference in AXB/BXA recombinant inbred mice: gender differences and gender-specific quantitative trait loci , 1998, Mammalian Genome.

[50]  J. Belknap,et al.  Genes on mouse Chromosomes 2 and 9 determine variation in ethanol consumption , 1998, Mammalian Genome.

[51]  R. Hitzemann,et al.  Genetics of ethanol-induced locomotor activation: detection of QTLs in a C57BL/6J × DBA/2J F2 intercross , 1998, Mammalian Genome.

[52]  C. Cunningham,et al.  Ethanol-induced conditioned taste aversion in BXD recombinant inbred mice. , 1998, Alcoholism, clinical and experimental research.

[53]  G. Mcclearn,et al.  Confirmation of quantitative trait loci for alcohol preference in mice. , 1998, Alcoholism, clinical and experimental research.

[54]  G F Koob,et al.  Drug dependence: stress and dysregulation of brain reward pathways. , 1998, Drug and alcohol dependence.

[55]  V. Erwin,et al.  Common quantitative trait loci for alcohol-related behaviors and CNS neurotensin measures: voluntary ethanol consumption. , 1998, Alcoholism, clinical and experimental research.

[56]  A. Nordberg,et al.  Chronic Ethanol Treatment Decreases [3H]Epibatidine and [3H]Nicotine Binding and Differentially Regulates mRNA Levels of Nicotinic Acetylcholine Receptor Subunits Expressed in M10 and SH‐SY5Y Neuroblastoma Cells , 1998, Journal of neurochemistry.

[57]  J. Crabbe,et al.  Quantitative Trait Loci Involved in Genetic Predisposition to Acute Alcohol Withdrawal in Mice , 1997, The Journal of Neuroscience.

[58]  S. Paul,et al.  Mapping Quantitative Trait Loci for Open-Field Behavior in Mice , 1997, Behavior genetics.

[59]  H. Steiner,et al.  Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin , 1996, Nature.

[60]  J. Crabbe.  Quantitative trait locus gene mapping: a new method for locating alcohol response genes , 1996, Addiction biology.

[61]  J. Xu,et al.  Structure and characterization of the gene encoding a mouse kappa3-related opioid receptor. , 1996, Gene.

[62]  J. Crabbe,et al.  Identification of genetic markers for initial sensitivity and rapid tolerance to ethanol-induced ataxia using quantitative trait locus analysis in BXD recombinant inbred mice. , 1996, The Journal of pharmacology and experimental therapeutics.

[63]  R. Deitrich,et al.  Voluntary alcohol consumption in BXD recombinant inbred mice: relationship to alcohol metabolism. , 1996, Alcoholism, clinical and experimental research.

[64]  C. Dourish,et al.  Behavioural and pharmacological characterisation of the elevated “zero-maze” as an animal model of anxiety , 1994, Psychopharmacology.

[65]  J. Crabbe,et al.  Quantitative trait loci mapping of genes that influence the sensitivity and tolerance to ethanol-induced hypothermia in BXD recombinant inbred mice. , 1994, The Journal of pharmacology and experimental therapeutics.

[66]  J. Crabbe.  Tolerance to ethanol hypothermia in HOT and COLD mice. , 1994, Alcoholism, clinical and experimental research.

[67]  J. Crabbe,et al.  Quantitative trait loci (QTL) applications to substances of abuse: Physical dependence studies with nitrous oxide and ethanol in BXD mice , 1993, Behavior genetics.

[68]  J. Crabbe,et al.  Mapping of a putative genetic locus determining ethanol intake in the mouse , 1987, Brain Research.

[69]  N. Schork,et al.  Identification of Quantitative Trait Loci for Anxiety and Locomotion Phenotypes in Rat Recombinant Inbred Strains , 2004, Behavior genetics.

[70]  Jonathan Flint,et al.  Analysis of quantitative trait loci that influence animal behavior. , 2003, Journal of neurobiology.

[71]  J. Crabbe,et al.  QTL Analysis and Genomewide Mutagenesis in Mice: Complementary Genetic Approaches to the Dissection of Complex Traits , 2001, Behavior genetics.

[72]  H. Little,et al.  Correlation between increases in dihydropyridine binding in vivo and behavioural signs of ethanol withdrawal in mice. , 1999, Alcohol and alcoholism.

[73]  J. Crabbe,et al.  Strategies for identifying genes underlying drug abuse susceptibility. , 1996, NIDA research monograph.