Genetic Analyses of Ethanol‐Induced Hyperglycemia

Risinger, Fred O.

doi:10.1097/01.alc.0000065697.73554.df

Cited by 6 publications

(5 citation statements)

References 33 publications

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“…Consistent with previous data (Risinger and Cunningham, 1991, 1992; Risinger, 2003), an acute ethanol injection induced a nominal, but non-significant increase in blood glucose levels (see Figure 3B). Blood glucose levels did not increase with repeated ethanol injections, and if anything, were lower in sensitized mice compared with controls.…”

Section: Discussionsupporting

confidence: 93%

“…Acute ethanol administration in normally feeding rodents results in a mild but prolonged hyperglycemia (Oliveira de Souza and Masur, 1981; Souza and Masur, 1982, 1984; Risinger and Cunningham, 1991, 1992; Risinger, 2003), due in part to increased glycogenolysis and decreased glyconeogenesis (see van de Wiel, 2004 for review). Ethanol also acutely inhibits signaling through the insulin receptor (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Insulin attenuates the acquisition and expression of ethanol-induced locomotor sensitization in DBA/2J mice

Kliethermes

Heberlein

2011

Life Sciences

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Aims Ethanol-induced locomotor sensitization is a behavioral manifestation of physiological responses to repeated ethanol exposures. While ethanol exerts direct effects on multiple neurotransmitter systems in the brain, ethanol-induced changes in metabolic state, including acute hyperglycemia and inhibition of insulin signaling, also have plausible roles in the expression of ethanol-related behaviors through direct and indirect effects on brain function. The current experiments examined whether insulin administration or the resultant hypoglycemia might attenuate the development of sensitization to the locomotor stimulant effect of ethanol. Main methods Male and female DBA/2J mice received daily injections of 5 or 10 IU/kg insulin before or after a stimulating dose of ethanol and subsequent testing in an automated activity monitor. Blood glucose levels were determined upon the completion of the experiments. Key findings Insulin injected prior to ethanol blunted the acute stimulant response as well as the acquisition and expression of locomotor sensitization, while insulin given after ethanol did not affect the development of the sensitized response. In a separate experiment, mice given glucose concurrently with insulin developed ethanol-induced locomotor sensitization normally. Significance These experiments suggest that insulin attenuates the development of ethanol-induced locomotor sensitization, and that blood glucose levels can largely account for this effect. Further studies of the role of ethanol-induced metabolic states should provide novel information on the expression of ethanol-related behaviors.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Insulin attenuates the acquisition and expression of ethanol-induced locomotor sensitization in DBA/2J mice

Kliethermes

Heberlein

2011

Life Sciences

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“…However, one distinction between ErGeN3 and ErGeN10 was the clustered connections of numerous ethanol relevant phenotypes to ErGeN10 . While ErGeN3 correlated with ethanol metabolism rate [67] and blood glucose levels following ethanol treatment [68] , ErGeN10 appears more related to ethanol behavioral phenotypes, including ethanol induced locomotor activation [63] , anxiolysis (Cook et al, unpublished) and sensitization [69] .…”

Section: Resultsmentioning

confidence: 99%

Genetic Dissection of Acute Ethanol Responsive Gene Networks in Prefrontal Cortex: Functional and Mechanistic Implications

et al. 2012

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BackgroundIndividual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol.ResultsAcute ethanol altered the expression of ∼2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol's effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity.Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3β, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3, Pten and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b, Gria1, Sncb and Nell2.ConclusionsThe ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders.

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“…In line with this, it is also possible that only testing 29 BXD strains is a limitation of our study. However, other studies have successfully used fewer numbers of strains for QTL analysis and identified significant loci 42‐45 …”

Section: Discussionmentioning

confidence: 99%

Systems genetic analysis of nicotine withdrawal deficits in hippocampus‐dependent learning

Goldberg

Kutlu

Zeid

et al. 2021

Genes Brain and Behavior

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Cognitive deficits, such as disrupted learning, are a major symptom of nicotine withdrawal. These deficits are heritable, yet their genetic basis is largely unknown. Our lab has developed a mouse model of nicotine withdrawal deficits in learning, using chronic nicotine exposure via osmotic minipumps and fear conditioning. Here, we utilized the BXD genetic reference panel to identify genetic variants underlying nicotine withdrawal deficits in learning. Male and female mice (n = 6–11 per sex per strain, 31 strains) received either chronic saline or nicotine (6.3 mg/kg per day for 12 days), and were then tested for hippocampus‐dependent learning deficits using contextual fear conditioning. Quantitative trait locus (QTL) mapping analyses using GeneNetwork identified a significant QTL on Chromosome 4 (82.13 Mb, LRS = 20.03, p < 0.05). Publicly available hippocampal gene expression data were used to identify eight positional candidates (Snacpc3, Mysm1, Rps6, Plaa, Lurap1l, Slc24a2, Hacd4, Ptprd) that overlapped with our behavioral QTL and correlated with our behavioral data. Overall, this study demonstrates that genetic factors impact cognitive deficits during nicotine withdrawal in the BXD recombinant inbred panel and identifies candidate genes for future research.

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Genetic Analyses of Ethanol‐Induced Hyperglycemia

Abstract: These findings indicate important sex differences in the glycemic response to ethanol. In addition, multiple genes likely control this response, independent from genes that are important for the thermic or aversive effects of ethanol.

Cited by 6 publications

References 33 publications

Insulin attenuates the acquisition and expression of ethanol-induced locomotor sensitization in DBA/2J mice

Insulin attenuates the acquisition and expression of ethanol-induced locomotor sensitization in DBA/2J mice

Genetic Dissection of Acute Ethanol Responsive Gene Networks in Prefrontal Cortex: Functional and Mechanistic Implications

Systems genetic analysis of nicotine withdrawal deficits in hippocampus‐dependent learning

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