1. ¹Research Service, Veterans Affairs Medical Center, Oregon Health and Science University, Portland, OR, USA
2. ²Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA
3. ³Department of Medicine, Oregon Health and Science University, Portland, OR, USA

Correspondence: Dr KM Wiren, OHSU, Portland VA Medical Center, Research Service, P3 R&D39, Portland, OR 97239, USA. Tel: 503 220 8262, ext. 56595; Fax: 503 273 5351; E-mail: wirenk@ohsu.edu

Received 14 August 2006; Revised 23 April 2007; Accepted 24 May 2007; Published online 27 June 2007.

Abstract

While women are more vulnerable than men to many of the medical consequences of alcohol abuse, the role of sex in the response to ethanol is controversial. Neuroadaptive responses that result in the hyperexcitability associated with withdrawal from chronic ethanol likely reflect gene expression changes. We have examined both genders for the effects of withdrawal on brain gene expression using mice with divergent withdrawal severity that have been selectively bred from a genetically heterogeneous population. A total of 295 genes were identified as ethanol regulated from each gender of each selected line by microarray analyses. Hierarchical cluster analysis of the arrays revealed that the transcriptional response correlated with sex rather than with the selected withdrawal phenotype. Consistent with this, gene ontology category over-representation analysis identified cell death and DNA/RNA binding as targeted classes of genes in females, while in males, protein degradation, and calcium ion binding pathways were more altered by alcohol. Examination of ethanol-regulated genes and these distinct signaling pathways suggested enhanced neurotoxicity in females. Histopathological analysis of brain damage following ethanol withdrawal confirmed elevated cell death in female but not male mice. The sexually dimorphic response was observed irrespective of withdrawal phenotype. Combined, these results indicate a fundamentally distinct neuroadaptive response in females compared to males during chronic ethanol withdrawal and are consistent with observations that female alcoholics may be more vulnerable than males to ethanol-induced brain damage associated with alcohol abuse.