Neurobeachin, a promising target for use in the treatment of alcohol use disorder.

Hazardous, heavy drinking increases risk for developing alcohol use disorder (AUD), which affects ~7% of adult Americans. Thus, understanding the molecular mechanisms promoting risk for heavy drinking is essential to developing more effective AUD pharmacotherapies than those currently approved by the FDA. Using genome-wide bisulfate sequencing, we identified DNA methylation (DNAm) signals within the nucleus accumbens core (NAcC) that differentiate nonheavy and heavy ethanol-drinking rhesus macaques. One differentially DNAm region (D-DMR) located within the gene neurobeachin (NBEA), which promotes synaptic membrane protein trafficking, was hypermethylated in heavy drinking macaques. A parallel study identified a similar NBEA D-DMR in human NAcC that distinguished alcoholic and nonalcoholic individuals. To investigate the role of NBEA in heavy ethanol drinking, we engineered a viral vector carrying a short hairpin RNA (shRNA) to reduce the expression of NBEA. Using two murine models of ethanol consumption: 4 days of drinking-in-the-dark and 4 weeks of chronic intermittent access, the knockdown of NBEA expression did not alter average ethanol consumption in either model. However, it did lead to a significant increase in the ethanol preference ratio. Following withdrawal, whole-cell patch clamp electrophysiological experiments revealed that Nbea knockdown led to an increase in spontaneous excitatory postsynaptic current amplitude with no alteration in spontaneous inhibitory postsynaptic currents, suggesting a specific role of NBEA in trafficking of glutamatergic receptors. Together, our findings suggest that NBEA could be targeted to modulate the preference for alcohol use.