Impact of Genetic Variation on Stress-Related Ethanol Consumption

Megan K. Mulligan, Lu Lu, Sonia Angele Cavigelli, Pierre Mormède, Elena Terenina, Wenyuan Zhao, Robert W. Williams, Byron C. Jones

Research output: Contribution to journalArticle

Abstract

Background: The effect of stress on alcohol consumption in humans is highly variable, and the underlying processes are not yet understood. Attempts to model a positive relationship between stress and increased ethanol (EtOH) consumption in animals have been only modestly successful. Our hypothesis is that individual differences in stress effects on EtOH consumption are mediated by genetics. Methods: We measured alcohol consumption, using the drinking-in-the-dark (DID) paradigm in females from 2 inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), and 35 of their inbred progeny (the BXD family). A control group was maintained in normal housing and a stress group was exposed to chronic mild stress (CMS), consisting of unpredictable stressors over 7 weeks. These included predator, social, and environmental perturbations. Alcohol intake was measured over 16 weeks in both groups during baseline (preceding 5-week period), CMS (intervening 7-week period), and post-CMS (final 4-week period). Results: We detected a strong effect of CMS on alcohol intake. A few strains demonstrated CMS-related increased alcohol consumption; however, most showed decreased intake. We identified 1 nearly significant quantitative trait locus on chromosome 5 that contains the neuronal nitric oxide synthase gene (Nos1). The expression of Nos1 is frequently changed following alcohol exposure, and variants in this gene segregating among the BXD population may modulate alcohol intake in response to stress. Conclusions: The results we present here represent the first study to combine chronic stress and alcohol consumption in a genetic reference population of mice. Differences in susceptibility to the effects of stressful environments vis-à-vis alcohol use disorders would suggest that the differences have at least some basis in genetic constitution. We have also nominated a likely candidate gene underlying the large individual differences in effects of stress on alcohol consumption.

Original languageEnglish (US)
Pages (from-to)1391-1402
Number of pages12
JournalAlcoholism: Clinical and Experimental Research
Volume43
Issue number7
DOIs
StatePublished - Jul 1 2019

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Alcohol Drinking
Ethanol
Alcohols
Individuality
Genes
Nitric Oxide Synthase Type I
Chromosomes, Human, Pair 5
Inbred Strains Mice
Quantitative Trait Loci
Constitution and Bylaws
Population Genetics
Drinking
Control Groups
Chromosomes
Population
Animals

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Mulligan, M. K., Lu, L., Cavigelli, S. A., Mormède, P., Terenina, E., Zhao, W., ... Jones, B. C. (2019). Impact of Genetic Variation on Stress-Related Ethanol Consumption. Alcoholism: Clinical and Experimental Research, 43(7), 1391-1402. https://doi.org/10.1111/acer.14073
Mulligan, Megan K. ; Lu, Lu ; Cavigelli, Sonia Angele ; Mormède, Pierre ; Terenina, Elena ; Zhao, Wenyuan ; Williams, Robert W. ; Jones, Byron C. / Impact of Genetic Variation on Stress-Related Ethanol Consumption. In: Alcoholism: Clinical and Experimental Research. 2019 ; Vol. 43, No. 7. pp. 1391-1402.
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abstract = "Background: The effect of stress on alcohol consumption in humans is highly variable, and the underlying processes are not yet understood. Attempts to model a positive relationship between stress and increased ethanol (EtOH) consumption in animals have been only modestly successful. Our hypothesis is that individual differences in stress effects on EtOH consumption are mediated by genetics. Methods: We measured alcohol consumption, using the drinking-in-the-dark (DID) paradigm in females from 2 inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), and 35 of their inbred progeny (the BXD family). A control group was maintained in normal housing and a stress group was exposed to chronic mild stress (CMS), consisting of unpredictable stressors over 7 weeks. These included predator, social, and environmental perturbations. Alcohol intake was measured over 16 weeks in both groups during baseline (preceding 5-week period), CMS (intervening 7-week period), and post-CMS (final 4-week period). Results: We detected a strong effect of CMS on alcohol intake. A few strains demonstrated CMS-related increased alcohol consumption; however, most showed decreased intake. We identified 1 nearly significant quantitative trait locus on chromosome 5 that contains the neuronal nitric oxide synthase gene (Nos1). The expression of Nos1 is frequently changed following alcohol exposure, and variants in this gene segregating among the BXD population may modulate alcohol intake in response to stress. Conclusions: The results we present here represent the first study to combine chronic stress and alcohol consumption in a genetic reference population of mice. Differences in susceptibility to the effects of stressful environments vis-{\`a}-vis alcohol use disorders would suggest that the differences have at least some basis in genetic constitution. We have also nominated a likely candidate gene underlying the large individual differences in effects of stress on alcohol consumption.",
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Mulligan, MK, Lu, L, Cavigelli, SA, Mormède, P, Terenina, E, Zhao, W, Williams, RW & Jones, BC 2019, 'Impact of Genetic Variation on Stress-Related Ethanol Consumption', Alcoholism: Clinical and Experimental Research, vol. 43, no. 7, pp. 1391-1402. https://doi.org/10.1111/acer.14073

Impact of Genetic Variation on Stress-Related Ethanol Consumption. / Mulligan, Megan K.; Lu, Lu; Cavigelli, Sonia Angele; Mormède, Pierre; Terenina, Elena; Zhao, Wenyuan; Williams, Robert W.; Jones, Byron C.

In: Alcoholism: Clinical and Experimental Research, Vol. 43, No. 7, 01.07.2019, p. 1391-1402.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Impact of Genetic Variation on Stress-Related Ethanol Consumption

AU - Mulligan, Megan K.

AU - Lu, Lu

AU - Cavigelli, Sonia Angele

AU - Mormède, Pierre

AU - Terenina, Elena

AU - Zhao, Wenyuan

AU - Williams, Robert W.

AU - Jones, Byron C.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Background: The effect of stress on alcohol consumption in humans is highly variable, and the underlying processes are not yet understood. Attempts to model a positive relationship between stress and increased ethanol (EtOH) consumption in animals have been only modestly successful. Our hypothesis is that individual differences in stress effects on EtOH consumption are mediated by genetics. Methods: We measured alcohol consumption, using the drinking-in-the-dark (DID) paradigm in females from 2 inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), and 35 of their inbred progeny (the BXD family). A control group was maintained in normal housing and a stress group was exposed to chronic mild stress (CMS), consisting of unpredictable stressors over 7 weeks. These included predator, social, and environmental perturbations. Alcohol intake was measured over 16 weeks in both groups during baseline (preceding 5-week period), CMS (intervening 7-week period), and post-CMS (final 4-week period). Results: We detected a strong effect of CMS on alcohol intake. A few strains demonstrated CMS-related increased alcohol consumption; however, most showed decreased intake. We identified 1 nearly significant quantitative trait locus on chromosome 5 that contains the neuronal nitric oxide synthase gene (Nos1). The expression of Nos1 is frequently changed following alcohol exposure, and variants in this gene segregating among the BXD population may modulate alcohol intake in response to stress. Conclusions: The results we present here represent the first study to combine chronic stress and alcohol consumption in a genetic reference population of mice. Differences in susceptibility to the effects of stressful environments vis-à-vis alcohol use disorders would suggest that the differences have at least some basis in genetic constitution. We have also nominated a likely candidate gene underlying the large individual differences in effects of stress on alcohol consumption.

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