We studied the involvement of norepinephrine in the medial prefrontal cortex in the rewarding/reinforcing effects of ethanol. We evaluated the effects of norepinephrine selective depletion in the medial prefrontal cortex of C57/BL6J inbred mice that are commonly used in molecular studies and are highly susceptible to the behavioral effects of ethanol. In mice with prefrontal norepinephrine depletion, ethanol did not induce conditioned place preference, and a clear-cut reduction of ethanol consumption and preference was evident. These results indicate that prefrontal norepinephrine transmission is a critical factor in the rewarding/reinforcing effects of ethanol.