Binge drinking changes the pattern of gene expression in an area of the brain called the nucleus accumbens (NAc), which is linked with addiction. A new study in mice by researchers at Oregon Health & Science University, and VA Portland Health Care System has now shown that gene expression changes that occur in response to binge drinking are very different in the NAc regions of males and females. Whereas in male mice the gene expression differences impacted on neurotransmitter metabolism and so nerve cell signalling, in females binge drinking-related changes to gene expression altered hormone signaling and immune function.

The results suggest that any future drug treatments for alcohol abuse disorders may need to be tailored towards males and females separately. In the reported studies the researchers found that pharmacologically manipulating a pathway that was affected by binge drinking only in male mice did reduce alcohol intake in male animals, but had no effect on female animals.

“Our results suggested repeated binge drinking had a very different effect on the neuroadaptive responses of the NAc in males and females, with different pathways being activated in each sex,” comments research head Debora A. Finn, Ph.D., a professor of behavioural neuroscience at Oregon Health & Science University and a research pharmacologist at the VA Portland Health Care System. “A consideration of sex is critical in the development of potential pharmacological therapies for the treatment of alcohol use disorder.”

The researchers report their findings in Frontiers in Genetics, in a paper titled, “Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice.”

Excessive use of alcohol is the fourth leading preventable cause of death in the U.S., and accounted for about 3.3 million lives in 2012, the authors write. About three quarters of the $249 billion in alcohol use disorder (AUD)-related costs in the U.S. in 2010 related to binge drinking and related consumption behaviors.

Binge drinking can lead to alcohol dependence, and previous research has found that the brains of male and female mice respond differently to alcohol withdrawal. To investigate whether binge drinking also results in sex-dependent changes in gene expression, Dr. Finn’s team used quantitative PCR (qPCR) to measure expression levels of 384 genes that had previously been identified as important in addiction and mood disorders, in the NAc of adult male and female mice, following seven binge ethanol drinking sessions. The drinking-related changes in gene expression were compared with gene expression levels in control mice that consumed just water.

The results showed that repeated binge drinking significantly changed the expression levels of 106 genes, including 56 genes only in females, 36 genes only in males, and 14 genes that were regulated in both sexes. However of these 14 genes, the expression of only 4 (Drd5, Grm4, Ranbp9, and Reln) was changed in the same direction. The other 10 genes were regulated in opposite directions in males and females. 

The sex-related changes to gene expression indicated that binge drinking had different effects on biochemical pathways in male and female animals. “In female mice, expression differences suggested that hormone signaling and immune function might be altered,” the authors write. “A different pattern of results was found for males, where expression difference suggested that neurotransmitter metabolism was altered by repeated binge drinking.”

An analysis of genes that were regulated in both males and females in response to repeated binge drinking pointed to three particular pathways of interest: CRH signalling, neuropathic pain signaling, and TNFR2 signaling. When the team used real-time qRT-PCR to look at the expression of genes involve in these pathways, they found that, again, repeated binge drinking had different effects in male and female mice. In females the CRH signaling pathway was inactivated, while in males it was activated. Repeated binge drinking resulted in sex-related differential regulation of glutamatergic and BDNF signaling genes involved in neuropathic pain signalling. Female mice, meanwhile, showed inactivation of the TNFR2 signaling pathway, while in males there was an upregulation of relevant genes.

“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,” the researchers conclude.

“Importantly, because we directly tested males and females following repeated binge drinking, the present results show for the first time that repeated binge drinking experience produces sexually divergent transcriptional responses and activation of distinct networks, similar to what has been reported for males and females tested during acute withdrawal following chronic intoxication,” the team notes. “These findings are important as they increase our understanding of male and female differences in molecular pathways and networks that can be influenced by repeated binge drinking,” Dr. Finn states. “This knowledge can help us identify and develop new targeted treatments for alcohol use disorder in males and female patients.”

The studies suggest that just a few genes may represent common binge-drinking targets in both male and female mice. The finding that only 4 of the 106 genes most significantly affect were regulated similarly in males and females demonstrates “a profound sex difference in neuroadaptive responses in the NAc that would result in dysregulation of distinct biological pathways between the sexes,” the authors add.  “An examination of the genes regulated by chronic intoxication in these pathways revealed that several of the genes in females were indicative of a proinflammatory response, while the genes in males were suggestive of overall immunosuppression…the results in females in the present study would be consistent with a decrease in cell survival, and an increase in apoptosis and inflammation via a decrease in the activation of the NF-kB.”

They further suggest that the observed relationships between genes was suggestive of a sex-related response that may also link with mood disorders. “A broader implication of the current findings is pertinent to sex differences in the immune system and the relationship to mood disorders…” Evaluaing the latest results in the context of prior research highlighting sex differences in mood and anxiety disorders, indicates that  “future studies examining potential immune or stress-related mechanisms that may contribute to stress and ethanol susceptibility and associated mood disorders will be important.”

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