The aim of this study was to investigate whether the DNA methylation pattern within the alpha synuclein promoter region is altered in intoxicated and early abstinence patients with alcoholism undergoing alcohol withdrawal. We observed a significant increase of the alpha synuclein promoter DNA methylation in patients with alcoholism which was significantly associated with their elevated homocysteine levels. No significant differences of the promoter DNA methylation within a control gene (presenilin-1) in alcoholics and controls were found. The present results hint to a gene specific DNA promoter hypermethylation within the alpha synuclein gene. Since hypermethylation of DNA is an important epigenetic factor in the down regulation of gene expression and since alpha synuclein has been linked to craving these findings may explain the reduced value of craving under alcohol drinking conditions.

There are well-known sex differences in the epidemiology and etiopathology of alcohol dependence. Male gender is a crucial risk factor for the onset of alcohol addiction. A directly modifying role of testosterone in alcohol addiction-related behavior is well established. Sex hormones exert both permanent (organizational) and transient (activational) effects on the human brain. The sensitive period for these effects lasts throughout life. In this article, we present a novel early sex hormone activity model of alcohol addiction. We propose that early exposure to sex hormones triggers structural (organizational) neuroadaptations. These neuroadaptations affect cellular and behavioral responses to adult sex hormones, sensitize the brain's reward system to the reinforcing properties of alcohol and modulate alcohol addictive behavior later in life. This review outlines clinical findings related to the early sex hormone activity model of alcohol addiction (handedness, the second-to-fourth-finger length ratio, and the androgen receptor and aromatase) and includes clinical and preclinical literature regarding the activational effects of sex hormones in alcohol drinking behavior. Furthermore, we discuss the role of the hypothalamic-pituitary-adrenal and -gonadal axes and the opioid system in mediating the relationship between sex hormone activity and alcohol dependence. We conclude that a combination of exposure to sex hormones in utero and during early development contributes to the risk of alcohol addiction later in life. The early sex hormone activity model of alcohol addiction may prove to be a valuable tool in the development of preventive and therapeutic strategies.