Neurodevelopmental liabilities in alcohol dependence: central serotonin and dopamine dysfunction.

Alcoholism is a complex disorder with symptoms ranging from abuse to dependence, often comorbid with depression, antisocial personality, or anxiety. Neurodevelopmental causes of the disorder are unknown but inferences are possible from current knowledge. Neurobiological studies implicate multiple brain changes, which may be characterized as premorbid or morbid. These studies have also examined specific aspects of the alcohol dependence syndrome, including alcohol reinforcement and craving. Here, we review the evidence for vulnerability factors in alcohol dependence, with an emphasis on central serotonin (5-HT) and dopamine (DA). Serotonin dysfunction likely contributes to the development of alcoholism since studies of alcohol-preferring rodents show decreased 5-HT function on many measures. We have shown that serotonin-enhancing drugs reduce consumption and craving in mild to moderate alcoholics, yet similar studies in severely dependent individuals remain inconclusive. Studies indicate that serotonin dysfunction may contribute to the development of dependence via impaired impulse control and/or mood regulation. The mesocorticolimbic dopamine pathway represents another important pathophysiological target in alcoholism. Differences in D(2) receptor density, dopamine sensitivity, and gene expression have been linked to consumption, reinforcement, craving, and relapse. However, while DA agonists reduce self-administration in animals, we found no effect in humans with long-acting bromocriptine, a D(2) agonist. Dopamine may contribute differentially to the development of dependence via its effects on alcohol wanting, reinforcement, and reward memory. Although animal experiments show consistent roles for serotonin and dopamine in alcohol dependence, human studies are not always concordant. Such discrepancies highlight the complexity of dependence-related behaviors in humans and of identifying vulnerabilities to alcoholism.