TY - JOUR
T1 - Binge ethanol drinking produces sexually divergent and distinct changes in nucleus accumbens signaling cascades and pathways in adult C57BL/6J mice
AU - Finn, Deborah A.
AU - Hashimoto, Joel G.
AU - Cozzoli, Debra K.
AU - Helms, Melinda L.
AU - Nipper, Michelle A.
AU - Kaufman, Moriah N.
AU - Wiren, Kristine M.
AU - Guizzetti, Marina
N1 - Funding Information:
This study was supported by VA Merit grants (BX001070 and BX002966 to DF) from the United States Department of Veterans Affairs and by resources and facilities at the VA Portland Health Care System (DF, KW, and MG). RO1 AA021468 (KW and MG) from the National Institute on Alcohol Abuse and Alcoholism provided additional support. We thank Mr. Chris Snelling for the assessment of blood ethanol concentration.
Publisher Copyright:
© 2018 Finn, Hashimoto, Cozzoli, Helms, Nipper, Kaufman, Wiren and Guizzetti.
PY - 2018/9/10
Y1 - 2018/9/10
N2 - We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average > 2.2 g/kg/30 min) and blood ethanol concentrations (average > 1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2, Fos, Nos1, and Star), and only 4 of the 14 genes were regulated in the same direction (Drd5, Grm4, Ranbp9, and Reln). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder.
AB - We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average > 2.2 g/kg/30 min) and blood ethanol concentrations (average > 1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2, Fos, Nos1, and Star), and only 4 of the 14 genes were regulated in the same direction (Drd5, Grm4, Ranbp9, and Reln). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder.
KW - Alcohol
KW - C57BL/6J mice
KW - Hormone signaling
KW - Immune function
KW - Neurotransmitter metabolism
KW - QPCR arrays
KW - Sex differences
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U2 - 10.3389/fgene.2018.00325
DO - 10.3389/fgene.2018.00325
M3 - Article
AN - SCOPUS:85053111647
SN - 1664-8021
VL - 9
JO - Frontiers in Genetics
JF - Frontiers in Genetics
IS - SEP
M1 - 325
ER -