Environmental exposure to heavy metals is one of the biggest concerns in public health. Manganese (Mn) in excess is neurotoxic and closely associated with impaired neurobehavioral functions. Our previous study has indicated that alcohol consumption increases olfactory Mn uptake to the brain, suggesting that alcohol could represent a risk factor for Mn-associated neurotoxicity. We here investigated the effect of alcohol drinking on neurobehavioral and neurochemical function in Mn-exposed mice. C57BL/6J mice (3-4 weeks old) were treated with either 10% (v/v) alcohol in drinking water or facility water for a total of 4 wks. One week after the start of alcohol drinking, mice were intranasally instilled with MnCl2 solution (5 mg/kg) daily for 3 wks, during which a series of neurobehavioral tests. Without alcohol treatment, Mn-instilled mice showed increased anxiety-like behavior, as assessed by elevated plus maze (EPM) and open field (OF) tests. Alcohol consumption synergistically increased anxiety-like behavior in Mn-instilled mice (17% increase by EPM and 62% increase by OF test) compared with water-drinking Mn-instilled mice. Since dopamine signaling is involved in emotional behavior, expression levels of dopamine-related proteins were quantified by western blot. Upon Mn instillation, alcohol-exposed mice significantly increased dopamine transporter levels (124% increase; p=0.007) and reduced dopamine D1 receptor (28% decrease; p=0.004) compared with water-drinking mice, likely attenuating dopamine signaling with alcohol consumption. Taken together, our results suggest that individuals who drink alcohol could increase the olfactory uptake of manganese into the brain and could be more susceptible to metal-induced neurotoxicity, likely due to altered dopaminergic neurotransmission.