Alcoholism: allostasis and beyond.

Alcoholism is a chronic relapsing disorder characterized by compulsive drinking, loss of control over intake, and impaired social and occupational function. Animal models have been developed for various stages of the alcohol addiction cycle with a focus on the motivational effects of withdrawal, craving, and protracted abstinence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drinking provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of alcoholism. Neuropharmacologic studies in animal models have provided evidence for specific neurochemical mechanisms in specific brain reward and stress circuits that become dysregulated during the development of alcohol dependence. The brain reward system implicated in the development of alcoholism comprises key elements of a basal forebrain macrostructure termed the extended amygdala that includes the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and a transition zone in the medial (shell) part of the nucleus accumbens. There are multiple neurotransmitter systems that converge on the extended amygdala that become dysregulated during the development of alcohol dependence, including gamma-aminobutyric acid, opioid peptides, glutamate, serotonin, and dopamine. In addition, the brain stress systems may contribute significantly to the allostatic state. During the development of alcohol dependence, corticotropin-releasing factor may be recruited, and the neuropeptide Y brain antistress system may be compromised. These changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for relapse in recovering alcoholics. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic alcohol ingestion with genetic vulnerability but also provides a key to translate advances in animal studies to the human condition.