Quantitative Trait Locus Mapping for Acute Functional Tolerance to Ethanol in the L × S Recombinant Inbred Panel

Bennett, Beth; Downing, Chris; Carosone-Link, Phyllis; Ponicsan, Heather; Ruf, Cathy; Johnson, Thomas E.

doi:10.1111/j.1530-0277.2006.00296.x

Cited by 23 publications

(16 citation statements)

References 29 publications

(35 reference statements)

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“…Herein, we have conducted a genomic analysis of the mesocorticolimbic system from Fyn knockout mice in the presence and absence of ethanol to determine gene expression patterns associated with LORR that may have underlying associations beyond a single null mutation. Our results suggest several gene network level alterations in Fyn null mice that may also contribute to the modulation of ethanol-induced LORR, a behavioral phenotype characterized by both initial sensitivity and acute functional tolerance [70,71]. …”

Section: Discussionmentioning

confidence: 99%

Fyn-Dependent Gene Networks in Acute Ethanol Sensitivity

Farris

Miles

2013

PLoS ONE

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Studies in humans and animal models document that acute behavioral responses to ethanol are predisposing factor for the risk of long-term drinking behavior. Prior microarray data from our laboratory document strain- and brain region-specific variation in gene expression profile responses to acute ethanol that may be underlying regulators of ethanol behavioral phenotypes. The non-receptor tyrosine kinase Fyn has previously been mechanistically implicated in the sedative-hypnotic response to acute ethanol. To further understand how Fyn may modulate ethanol behaviors, we used whole-genome expression profiling. We characterized basal and acute ethanol-evoked (3 g/kg) gene expression patterns in nucleus accumbens (NAC), prefrontal cortex (PFC), and ventral midbrain (VMB) of control and Fyn knockout mice. Bioinformatics analysis identified a set of Fyn-related gene networks differently regulated by acute ethanol across the three brain regions. In particular, our analysis suggested a coordinate basal decrease in myelin-associated gene expression within NAC and PFC as an underlying factor in sensitivity of Fyn null animals to ethanol sedation. An in silico analysis across the BXD recombinant inbred (RI) strains of mice identified a significant correlation between Fyn expression and a previously published ethanol loss-of-righting-reflex (LORR) phenotype. By combining PFC gene expression correlates to Fyn and LORR across multiple genomic datasets, we identified robust Fyn-centric gene networks related to LORR. Our results thus suggest that multiple system-wide changes exist within specific brain regions of Fyn knockout mice, and that distinct Fyn-dependent expression networks within PFC may be important determinates of the LORR due to acute ethanol. These results add to the interpretation of acute ethanol behavioral sensitivity in Fyn kinase null animals, and identify Fyn-centric gene networks influencing variance in ethanol LORR. Such networks may also inform future design of pharmacotherapies for the treatment and prevention of alcohol use disorders.

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Section: Discussionmentioning

confidence: 99%

Fyn-Dependent Gene Networks in Acute Ethanol Sensitivity

Farris

Miles

2013

PLoS ONE

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Crabbe¹,

Colville

Kruse

et al. 2012

Alcoholism Clin & Exp Res

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Background Mouse lines are being selectively bred in replicate for high blood ethanol concentrations (BECs) achieved after limited access of ethanol (EtOH) drinking early in the circadian dark phase. High Drinking in the Dark -1 (HDID-1) mice are in selected generation S21, and the replicate HDID-2 line in generation S14. Tolerance and withdrawal symptoms are two of the seven diagnostic criteria for alcohol dependence. Withdrawal severity has been found in mouse studies to be negatively genetically correlated with EtOH preference drinking. Methods To determine other traits genetically correlated with high DID, we compared naive animals from both lines with the unselected, segregating progenitor stock, HS/Npt. Differences between HDID-1 and HS would imply commonality of genetic influences on DID and these traits. Results Female HDID-1 and HDID-2 mice tended to develop less tolerance than HS to EtOH hypothermia after their 3rd daily injection. A trend toward greater tolerance was seen in the HDID males. HDID-1, HDID-2 and control HS lines did not differ in the severity of acute or chronic withdrawal from EtOH as indexed by the handling-induced convulsion (HIC). Both HDID-1 and HDID-2 mice tended to have greater HIC scores than HS regardless of drug treatment. Conclusions These results show that tolerance to EtOH's hypothermic effects may share some common genetic control with reaching high BECs after DID, a finding consistent with other data regarding genetic contributions to ethanol responses. Withdrawal severity was not negatively genetically correlated with DID, unlike its correlation with preference drinking, underscoring the genetic differences between preference drinking and DID. HDID lines showed greater basal HIC scores than HS, suggestive of greater central nervous system excitability.

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“…One goal of QTL mapping is to determine the gene(s) responsible for the QTL, that is, the quantitative trait gene. Published QTL maps for different alcohol-related behaviors include acute functional tolerance, loss of righting reflex, taste aversion, withdrawal severity, voluntary consumption and conditioned place preference (103, 105–107). Nevertheless, for the behavioral effects of alcohol, this time- and resource-intensive process has been completed to the greatest extent for alcohol withdrawal severity (6, 108).…”

Section: Preclinical Strategies For Identification Of Novel Targmentioning

confidence: 99%

Molecular Targets of Alcohol Action

Gorini

Bell

Mayfield

2011

Progress in Molecular Biology and Translational Science

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Summary Alcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented.

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Quantitative Trait Locus Mapping for Acute Functional Tolerance to Ethanol in the L × S Recombinant Inbred Panel

Cited by 23 publications

References 29 publications

Fyn-Dependent Gene Networks in Acute Ethanol Sensitivity

Fyn-Dependent Gene Networks in Acute Ethanol Sensitivity

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

Molecular Targets of Alcohol Action

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