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

Abstract

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 The ethanol was next withdrawn and the withdrawal severity was assessed.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.

Ethanol Tolerance and Withdrawal Severity in High Drinking in the Dark Selectively Bred Mice

“…The literature on this topic is large, and has not been reviewed systematically for many years (Phillips, Crabbe 1991). Sensitivity and withdrawal severity are not generally correlated (Crabbe et al 1983;Crabbe et al 1994;Drews et al 2010). Chronic tolerance and dependence (i.e., withdrawal severity) may be negatively genetically coupled, but the evidence for this is also mixed [Crabbe 1996;Crabbe et al 1988;Crabbe et al 1983;Drews et al 2010); for review, see (Crabbe et al in press)].…”

“…Sensitivity and withdrawal severity are not generally correlated (Crabbe et al 1983;Crabbe et al 1994;Drews et al 2010). Chronic tolerance and dependence (i.e., withdrawal severity) may be negatively genetically coupled, but the evidence for this is also mixed [Crabbe 1996;Crabbe et al 1988;Crabbe et al 1983;Drews et al 2010); for review, see (Crabbe et al in press)]. Overall, it is likely that the genetic relationships among sensitivity, tolerance and dependence vary somewhat not only with the behaviors and the specific forms of tolerance studied but also with the specific genetic animal models employed (Radcliffe et al 2004;Deitrich et al 2000).…”

“…However, there is also evidence that acute and rapid tolerance may share some genetic determinants (Radcliffe et al 2006). Sensitivity and tolerance are sometimes positively genetically correlated in that strains and selected lines more sensitive to an EtOH effect tend to develop more tolerance (Deitrich 1993;Crabbe et al 1982;Phillips, Crabbe 1991) but not all findings are consistent [e.g., (Radcliffe et al 2005;Deitrich et al 2000;Gehle, Erwin 2000;Aufrere et al 1994;Drews et al 2010;Bennett et al 2007)]. The literature on this topic is large, and has not been reviewed systematically for many years (Phillips, Crabbe 1991).…”

Rodent Models of Genetic Contributions to Motivation to Abuse Alcohol

“…Thus, further progress involves specialized tools that narrow the QTL interval, eliminating regions at both ends until only a few genes remain plausible candidates. Such studies have continued in both mice and rats (Bice et al, 2011; Bice et al, 2010; Drews et al, 2010; Izidio et al, 2011; Ehlers et al, 2010). Some QTL studies target ethanol conditioned taste aversion and ethanol conditioned place preference: these also have been reviewed (Cunningham & Phillips, 2003; Cunningham et al, 2006).…”

Dysregulation of leukocyte gene expression in women with medication-refractory depression versus healthy non-depressed controls

“…Women have a higher lifetime prevalence of depression than men [3] and the duration of treatment-induced remission is shorter for women than men [2]. Also, human postmortem studies of regional brain mRNA markers in depression have identified different patterns in females vs. males [4,5]. Consequently, one strategy to reduce heterogeneity when studying depressed patients employed by several recent studies is to focus exclusively on females [6-8].…”