Pharmacogenetic studies of alcohol self-administration and withdrawal

Crabbe, John C.; Phillips, Tamara J.

doi:10.1007/s00213-003-1608-6

Cited by 32 publications

(23 citation statements)

References 210 publications

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“…4A). Separation between the genotypes was most pronounced at the two highest alcohol concentrations at which consumption motivated by pharmacological alcohol effects is known to dominate over intake for taste, calories, or other nonpharmacological effects (25). Preference for alcohol was also differentially affected (Fig.…”

Section: Alcohol Consumption and Preference Are Elevated In Mglur2 Nullmentioning

confidence: 96%

Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Zhou¹,

Karlsson

Liang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

107

116

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Identification of genes influencing complex traits is hampered by genetic heterogeneity, the modest effect size of many alleles, and the likely involvement of rare and uncommon alleles. Etiologic complexity can be simplified in model organisms. By genomic sequencing, linkage analysis, and functional validation, we identified that genetic variation of Grm2, which encodes metabotropic glutamate receptor 2 (mGluR2), alters alcohol preference in animal models. Selectively bred alcohol-preferring (P) rats are homozygous for a Grm2 stop codon (Grm2 *407) that leads to largely uncompensated loss of mGluR2. mGluR2 receptor expression was absent, synaptic glutamate transmission was impaired, and expression of genes involved in synaptic function was altered. Grm2 *407 was linked to increased alcohol consumption and preference in F2 rats generated by intercrossing inbred P and nonpreferring rats. Pharmacologic blockade of mGluR2 escalated alcohol self-administration in Wistar rats, the parental strain of P and nonpreferring rats. The causal role of mGluR2 in altered alcohol preference was further supported by elevated alcohol consumption in Grm2 −/− mice. Together, these data point to mGluR2 as an origin of alcohol preference and a potential therapeutic target. gene identification | selectively bred linesA lcoholism is a moderately to highly heritable disease (1, 2).The search for genetic variation influencing this complex disorder has yielded limited success. In human populations, candidate gene analyses have established roles for polymorphisms of ADH1B and ALDH2, both enzymes involved in alcohol metabolism (3). Genome-wide association studies (4-7) have implicated several genomic regions. However, the genes and functional variants that account for the genetic association signals remain largely unknown. Complex behavioral disorders may be influenced by many different genes. Most functional alleles are rare or uncommon, also contributing to genetic heterogeneity that hampers locus identification in population samples. Individual variants influencing alcoholism are also likely to be probabilistic in their actions, with limited effect sizes on risk of the disease itself. All of these factors pose significant challenges for identification of genes and functional variants contributing to alcoholism by population-based analyses in people.Model organisms, including selectively bred lines (8-10), offer a potentially powerful framework for genomic analyses to identify genes and their functional variants that contribute to complex disorders. The selective breeding process reduces genetic heterogeneity and enriches to high frequency variants that influence the targeted phenotype. Alcohol-preferring (P) and nonpreferring (NP) rats, a seminal rat model of alcoholism, were bred from Wistar rats by 30-70 generations of bidirectional selection for alcohol preference. These rats model human alcoholism in several ways. They voluntarily consume excessive amounts of alcohol with sustained high blood alcohol concentrations, consume alcohol fo...

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Section: Alcohol Consumption and Preference Are Elevated In Mglur2 Nullmentioning

confidence: 96%

Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Zhou¹,

Karlsson

Liang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

107

116

View full text Add to dashboard Cite

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“…C57BL/6J mice have a genetically determined high preference for ethanol-containing solutions (Bachmanov et al, 2002;Crabbe and Phillips, 2004) in nonoperant (Bachmanov et al, 2000;Belknap et al, 1993;McClearn and Rodgers, 1959;Rhodes et al, 2007;Yoneyama et al, 2008) and operant oral self-administration procedures (Elmer et al, 1988;Risinger et al, 1998). In this strain of mice, nonsweetened alcoholic solutions offered in operant procedures have marked reinforcing properties in long sessions (lasting 16 to 23 h) (Besheer et al, 2004Hodge et al, 2006;Risinger et al, 1998Risinger et al, , 2001Schroeder et al, 2003) and in foodrestricted mice (Elmer et al, 1986(Elmer et al, , 1988Middaugh et al, 1999;Hayward et al, 2004;Heidbreder et al, 2007).…”

Section: Introductionmentioning

confidence: 95%

Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABAB receptors

et al. 2012

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“…Animal models have been employed to examine the underlying neural mechanisms which may mediate alcohol dependence (Kaun et al, 2011; Spanagel, 2003). Laboratory animal species such as the mouse, rat, and fruit fly have been used to model alcohol-dependent behaviours such as conditioned place preference and alcohol-induced withdrawal symptoms (Spanagel, 2010; Crabbe & Phillips, 2004; Crabbe et al, 2010; Kaun et al, 2011). Two neuroplastic changes that are commonly examined following long-term alcohol use are the development of tolerance and sensitization (reverse tolerance) (Hyman & Malenka, 2001; Spanagel, 2010).…”

Section: Introductionmentioning

confidence: 99%

Recent advances with a novel model organism: Alcohol tolerance and sensitization in zebrafish (Danio rerio)

Tran

2014

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Alcohol abuse and dependence is a rapidly growing problem with few treatment options available. The zebrafish has become a popular animal model for behavioural neuroscience. This species may be appropriate for investigating the effects of alcohol on the vertebrate brain. In the current review, we examine the literature by discussing how alcohol alters behaviour in zebrafish and how it may affect biological correlates. We focus on two phenomena that are often examined in the context of alcohol-induced neuroplasticity. Alcohol tolerance (a progressive decrease in the effect of alcohol over time) is often observed following continuous (chronic) exposure to low concentrations of alcohol. Alcohol sensitization also called reverse tolerance (a progressive increase in the effect of alcohol over time) is often observed following repeated discrete exposures to higher concentrations of alcohol. These two phenomena may underlie the development and maintenance of alcohol addiction. The phenotypical characterization of these responses in zebrafish may be the first important steps in establishing this species as a tool for the analysis of the molecular and neurobiological mechanisms underlying human alcohol addiction.

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Pharmacogenetic studies of alcohol self-administration and withdrawal

Cited by 32 publications

References 210 publications

Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABAB receptors

Recent advances with a novel model organism: Alcohol tolerance and sensitization in zebrafish (Danio rerio)

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