The most longstanding theory of alcohol adaptation is chronic tolerance(2–7), i.e., the need for markedly increased amounts of alcohol to achieve a desired effect or experiencing markedly diminished effects with continued use of the same amount of alcohol. Tolerance, a diagnostic criteria for AUD from DSM-III (1980) to DSM-5 (2013)(8), implies that attenuation of subjective alcohol responses over time plays a key role in the development of addiction. In contrast, the sensitization theory asserts that greater stimulant effects over time underlie addictive processes(9), based on rodent data showing that stimulant-like and locomotor alcohol responses increase after repeated exposures(10, 11). These effects are particularly strong in selectively bred mouse lines (12–14) sensitized responses may also include adrenal hormones(15). The incentive-sensitization theory of addiction(16, 17) also emphasizes sensitization process, but specifies that repeated use of a drug produces neuroadapations that sensitize motivational reward to drugs and associated drug stimuli (i.e.., processes of “wanting”) distinct from the neurocircuitry mediating hedonic reward (liking) which may not sensitize over time. Finally, allostatic theory asserts heightened brain reward sensitivity and positive reinforcement characterize the early stages
