The march toward alcoholism is a multifaceted and dynamic process. It is characterized by an ever-progressing cycle of anticipation of use, positive reinforcement during intoxication, and a withdrawal-induced negative affective state that, fueled by stress, drives relapse and, ultimately, excessive alcohol consumption. How does one untie this Gordian knot? A good place to start might be targeting a brain region involved in relapse that is stress-sensitive, bi-directionally modulates motivated behavior, and interfaces multiple circuits encoding affect. Thanks to early work, the bed nucleus of the stria terminalis (BNST), which is part of the extended amygdala, fits the bill.

Supporting a role for the BNST in the development of alcohol use disorders is that BNST synapses are under plastic control by alcohol. Chronic alcohol exposure and acute withdrawal upregulate extrasynaptic GluN2B-containing NMDA receptors, which are necessary for BNST long-term synaptic potentiation (LTP) [1]. Supporting the notion that targeting BNST NMDA receptors modulates alcohol withdrawal-induced negative affective states is the finding that ketamine, an NMDA receptor antagonist with rapid-acting antidepressant effects, acutely attenuates depressive-like behavior following withdrawal from alcohol [2].

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