This article discusses the neurocircuitry and the neurochemical systems, as well as the molecular elements within these systems, that are believed to be important in the etiology of alcoholism. Alcoholism is a complex behavioral disorder characterized by excessive consumption of alcohol; a narrowing of the behavioral repertoire toward excessive consumption; the development of tolerance and dependence; and impairment in social and occupational functioning. Animal models of the complete syndrome of alcoholism are difficult if not impossible to achieve, but validated animal models exist for many of the different components of the syndrome.

Recent work has begun to define the neurocircuits responsible for the major sources of positive and negative reinforcement that are key to animal models of excessive alcohol intake. Alcohol appears to interact with alcohol-sensitive elements within neuronal membranes that convey the specificity of neurochemical actions. Positive reinforcement appears to be mediated by an activation γ-aminobutyric acid A receptors, release of opioid peptides and dopamine, inhibition of glutamate receptors, and interaction with serotonin systems. These neurocircuits may be altered by chronic alcohol administration. This is reflected by their exhibiting opposite effects during acute alcohol withdrawal, and by the recruitment of other neurotransmitter systems, such as the stress neuropeptide corticotropin-releasing factor. These neuropharmacologic actions are believed to produce allostatic changes in set-point, which set up the vulnerability to relapse that is so characteristic of alcoholism. Future challenges include a focus on understanding exactly how these neuroadaptive changes convey vulnerability to relapse in animals with a history of alcohol dependence.

Repeated episodes of alcohol withdrawal may exacerbate the severity of future withdrawal occurrences. The progressive intensification of withdrawal symptoms may be manifested as a kindling-like mechanism. This sensitization process may reflect persistent perturbation in excitatory and inhibitory influences on brain function. Relapse is also thought to be affected by the kindling mechanism. Successive alcohol withdrawal experiences may also lead to neurologic damage and cognitive impairments. We review the research findings regarding the alcohol withdrawal kindling hypothesis and the implications of the kindling process on mechanisms of dependence, alcohol withdrawal treatment strategies, and the long-term repercussions of alcoholism.

Alcoholism can result in a number of severe consequences to the central nervous system, including Korsakoff's psychosis, delusions, delirium, Wernicke's encephalopathy, and cerebellar degeneration. Many of these disorders have a substantially higher prevalence than had been previously believed. Neuropathologic and neuroimaging studies have been instrumental in identifying the changes undergone by the alcoholic brain and the factors that may contribute to alcohol-induced brain damage. Biologic differences appear to make women especially susceptible to central nervous system insult from alcohol abuse. The damage caused by alcohol may be associated, in part, with thiamine deficiency, neuronal excitotoxicity, and magnesium wasting.

Some of the profound effects alcohol has on the brain were discovered years ago through pathological studies at autopsy. However, the recent development of new tools for structural and functional brain imaging has enabled researchers to expand upon this earlier knowledge. For example, some imaging studies have revealed that chronic alcohol consumption causes cortical loss, some of which is reversible with abstinence. Other studies have found that alcohol acts as a global central nervous system depressant, with chronic use resulting in reduced activity that can take a month or more to recover. Finally, imaging tools are also beginning to shed light on which brain regions are active when an alcoholic has the urge to drink.

The excessive and chronic use of alcohol is associated with a variety of neurocognitive changes in a substantial number of detoxified alcoholics. These deficits extend across a wide variety of neuropsychological domains and can be observed over a period of months following detoxification. Furthermore, they are seen in both male and female alcoholics, despite the fact that female alcoholics often have shorter drinking histories. Although these deficits are widely observed, there is considerable heterogeneity both within and across studies. Currently, the sources of this variability are only poorly understood. In this article, we review these neurocognitive and neurophysiological deficits, their pattern of recovery, potential contributing or confounding factors, and some of the clinical implications of these findings.