The Genetics of Acute Functional Tolerance and Initial Sensitivity to Ethanol for an Ataxia Test in the LSxSS RI Strains

Vm, Gehle; Vg, Erwin

doi:10.1111/j.1530-0277.2000.tb02028.x

Cited by 20 publications

(20 citation statements)

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“…Likewise, too few measurements of the drug concentration also complicate this assessment especially when drug concentrations are rapidly changing Dietrich et al 2000;Gehle and Erwin 2000;Rustay et al 2001). Furthermore, venous blood measurements of the drug concentration often do not reflect the drug concentration in the brain (Wu et al 2001;.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous investigators have recognized that measures of initial sensitivity often represent a mixture of sensitivity and acute tolerance development (SanMarina et al 1989;Khanna et al 1990;Khanna et al 1991;Ramsay and Woods 1997;Dietrich et al 2000;Gehle and Erwin 2000;Ponomarev and Crabbe 2002). Research investigating how initial drug sensitivity, acute tolerance and chronic tolerance are related is susceptible to finding spurious associations because a baseline value can influence the size of the drug effect (sensitivity) that in turn can influence the amount of acute and chronic tolerance that can develop.…”

Section: Discussionmentioning

confidence: 99%

“…Schuckit and colleagues (2001) estimate that approximately 40% of children of alcoholics are relatively insensitive to ethanol while only 10% of children of non-alcoholics have this characteristic. Animal research has investigated whether these initial intrasessional factors are associated with subsequent chronic tolerance development or drug consumption by using rodents from outbred and inbred strains, as well as knock-out mice and selectively bred lines for drug consumption, drug sensitivity, and acute tolerance [e.g., outbred strains (Tabakoff and Culp 1984;San-Marina et al 1989;Khanna et al 1990b;Khanna et al 1991); inbred strains (Crabbe et al 1982;Tabakoff and Culp 1984;Khanna et al 1990a;Crabbe et al 1994;Gehle and Erwin 2000); knock-out mice (Naassila et al 2002); lines selectively bred for consumption (Tampier and Mardones 1999;Tampier et al 2000;Bell et al 2001); lines selectively bred for sensitivity (Khanna et al 1985;Crabbe et al 1989;Limm andCrabbe 1992: Crabbe 1994;Browman et al 2000;Deitrich et al 2000;Draski et al 2001;Palmer et al 2002); lines selectively bred for acute tolerance (Deitrich et al 2000;Rustay et al 2001;Wu et al 2001)]. While the scientific literature is in general agreement that initial sensitivity and acute tolerance are relevant to the subsequent development of chronic tolerance and drug consumption, a coherent description of this relationship has not emerged.…”

Section: Discussionmentioning

confidence: 99%

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Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats

2005

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Rationale: A preventive strategy for drug addiction would benefit from being able to identify vulnerable individuals. Understanding how an individual responds during an initial drug exposure may be useful for predicting how that individual will respond to repeated drug administrations.Objectives: This study investigated whether individual differences in initial drug sensitivity and acute tolerance can predict how chronic tolerance develops.Methods: During an initial 3-h administration of 60% nitrous oxide (N 2 O), male Long-Evans rats were screened for N 2 O's hypothermic effect into subsets based on being initially insensitive (II), sensitive with acute tolerance (AT), or sensitive with no intrasessional recovery (NR). Animals in each individual difference category were randomly assigned to receive six 90-min exposures of either 60% N 2 O or placebo gas. Core temperature was measured telemetrically.Results: Rats that exhibited a comparable degree of hypothermia during an initial N 2 O exposure, but differed in acute tolerance development, developed different patterns of chronic tolerance. Specifically, the NR group did not become fully tolerant over repeated N 2 O exposures while the AT group developed an initial hyperthermia followed by a return of core temperature to control levels indicative of full tolerance development. By the second N 2 O exposure, the II group breathing N 2 O became hyperthermic relative to the placebo control group and this hyperthermia persisted throughout the multiple N 2 O exposures.Conclusions: Individual differences in initial drug sensitivity and acute tolerance development predict different patterns of chronic tolerance. The hypothesis is suggested that individual differences in opponent adaptive responses may mediate this relationship.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats

2005

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“…There are various behavioral tests of ethanol-induced ataxia. They include the stationary dowel, the Rotarod, the screen test, and the grid test involving measures of grip strength, balance, and coordinated movement Phillips et al, 1996;Browman and Crabbe, 2000;Deitrich et al, 2000;Gehle and Erwin, 2000). Although inbred strains of mice have been shown to differ on numerous measures of ethanol sensitivity, no one strain has been shown to be more or less sensitive across all tests of ethanol sensitivity (Crabbe, 1983;Crabbe et al, 1994).…”

Section: Tablementioning

confidence: 99%

“…Ethanol-induced ataxia is clinically important and a good measure of intoxication. Several studies using various measures of ataxia have shown differences in initial sensitivity and acute tolerance across inbred strains Browman and Crabbe, 2000;Deitrich et al, 2000;Gehle and Erwin, 2000;Kirstein and Tabakoff, 2001). The dowel test for ataxia is a fairly simple test of coordination and balance that allows for the measurement of both initial sensitivity and acute tolerance to ethanol.…”

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confidence: 99%

Quantitative Trait Loci Affecting Initial Sensitivity and Acute Functional Tolerance to Ethanol-Induced Ataxia and Brain cAMP Signaling in BXD Recombinant Inbred Mice

Kirstein

Davidson²,

Ehringer³

et al. 2002

J Pharmacol Exp Ther

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In previous work, we identified genetic correlations between cAMP accumulation in the cerebellum and sensitivity to the incoordinating effects of ethanol. A genetic correlation suggests that common genes underlie the phenotypes investigated. One method for provisionally identifying genes involved in a given phenotypic measure is quantitative trait locus (QTL) analysis. Using a panel of 30 BXD recombinant inbred strains of mice and the progenitors (DBA/2J and C57BL/6J), and the dowel test for ataxia, we measured the blood ethanol concentrations at the time an animal first fell from the dowel and acute functional tolerance (AFT), and investigated cAMP signaling in the cerebellum. Cyclic AMP accumulation was measured in whole-cell preparations of cerebellar minces from individual mice under basal or stimulated conditions. We conducted a genome-wide QTL analysis of the behavioral and biochemical measures with Ͼ2000 genetic markers to identify significant associations. Western blot and comparative sequencing analysis were used to compare cAMP response element binding protein (CREB) levels and protein-coding sequence, respectively. QTL analyses correlating strain means with allelic status at genetic markers identified several significant associations (p Ͻ 0.01). Analysis of variance revealed an effect of strain on behavioral and biochemical measures. There was a significant genetic correlation between initial sensitivity and basal cAMP accumulation in the cerebellum. We identified 6 provisional QTLs for initial sensitivity on four chromosomes, 6 provisional QTLs for AFT on four chromosomes, and 11 provisional QTLs for cAMP signaling on nine chromosomes. Two loci were found to overlap for measures of initial sensitivity and for cAMP signaling. Given the genetic correlation between initial sensitivity and basal cAMP accumulation, we investigated candidate genes in a QTL on chromosome 1. Comparative sequence analysis was performed, and protein levels were compared between C57 and DBA mice for Creb1. No significant differences were detected in coding sequence or protein levels for CREB. These results suggest that although ethanol sensitivity and cAMP signaling are determined by multiple genes, they may share certain genetic codetermination.

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Overview of Mouse Assays of Ethanol Intoxication

et al. 2008

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There are many behavioral assays to assess sensitivity to ethanol intoxication in mice. Most are simple to implement, and are sensitive to a particular dose range of ethanol. Most reflect genetic influences, and each test appears to reflect the contribution of a relatively distinct collection of genes. This genetic heterogeneity implies that no single test can claim to capture the construct "ethanol intoxication" completely. Depending on the test, and when measurements are made, acute functional tolerance to even a single dose of ethanol must be considered as a contributing factor. Whether or not a test is conducted in naïve mice or as part of a test battery can influence sensitivity, and do so in a strain-dependent manner. This unit reviews existing tests and recommends several.

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The Genetics of Acute Functional Tolerance and Initial Sensitivity to Ethanol for an Ataxia Test in the LSxSS RI Strains

Cited by 20 publications

References 32 publications

Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats

Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats

Quantitative Trait Loci Affecting Initial Sensitivity and Acute Functional Tolerance to Ethanol-Induced Ataxia and Brain cAMP Signaling in BXD Recombinant Inbred Mice

Overview of Mouse Assays of Ethanol Intoxication

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