Dysregulation of brain stress systems mediates compulsive alcohol drinking

•Disruption of HPA axis leads to reward system hypofunction in alcohol dependence.•Extrahypothalamic stress systems are sensitized in alcohol dependence.•Loss of reward and stress sensitization drive compulsive alcohol drinking.

The transition from moderate to compulsive alcohol drinking is driven by increasingly dysfunctional reward and stress systems. We review behavioral and pharmacological studies of alcohol self-administration in rats that were mainly conducted within the framework of the alcohol vapor model of dependence. We discuss neurotransmitter systems that are implicated in alcohol drinking, with a focus on contrasting those neurotransmitter systems that drive behavior in the dependent versus nondependent states. We hypothesize that the identification of systems that become increasingly dysfunctional in alcohol dependence will reveal possible targets for successful interventions to reduce the motivation that drives compulsive alcohol drinking. In our opinion, drugs that normalize, rather than block, a hypofunctional reward system by restoring the function of hypothalamic stress systems and desensitize extrahypothalamic stress systems have the potential to selectively and effectively curb compulsive alcohol drinking.

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