While controversial, some researchers propose that ethanol functions as a prodrug, with brain-generated acetaldehyde potentially driving alcohol’s reinforcing effects (142). Preclinical studies using gene-specific modifications in the ventral tegmental area (VTA), a key midbrain region regulating reward, motivation, learning, and memory, support this hypothesis. Reducing brain-generated acetaldehyde by silencing catalase or increasing ALDH2 activity in the VTA decreases alcohol-induced-reinforcing effects and reduces voluntary ethanol intake (141). Conversely, increasing acetaldehyde production by expressing the hepatic enzyme ADH1B1 in the VTA enhances alcohol reinforcement and facilitates the initial acquisition of voluntary ethanol intake (141).
