α-Synuclein (α-syn) protein and endocannabinoid CB1 receptors are primarily located in presynaptic terminals. An association between α-syn and CB1 receptors has recently been established in Parkinson's disease, but it is completely unknown whether there is an association between these two proteins in alcohol addiction. Therefore, we aimed to examine the α-syn mRNA transcript and protein expression levels in the prefrontal cortex, striatum, amygdala and hippocampus. These brain regions are the most frequently implicated in alcohol and other drug addiction. In these studies, we used C57BL/6 mice carrying a spontaneous deletion of the α-syn gene (C57BL/6Snca-/-) and their respective controls (C57BL/6Snca+/+). These animals were monitored for spontaneous alcohol consumption (3–10%) and their response to a hypnotic-sedative dose of alcohol (3 g kg−1) was also assessed. Compared with the C57BL/6Snca+/+ mice, we found that the C57BL/6Snca-/- mice exhibited a higher expression level of the CB1 mRNA transcript and CB1 receptor in the hippocampus and amygdala. Furthermore, C57BL/6Snca-/- mice showed an increase in alcohol consumption when offered a 10% alcohol solution. There was no significant difference in sleep time after the injection of 3 g/kg alcohol. These results are the first to reveal an association between α-syn and the CB1 receptor in the brain regions that are most frequently implicated in alcohol and other drug addictions. Synapse 00:000–000, 2013. © 2013 Wiley Periodicals, Inc.