Alcohol and stress in the brain: how CRF drives relapse
Why do people who have quit drinking so often relapse when they're under stress? New brain research maps a specific molecular circuit that links stress to alcohol craving, and shows how alcohol actively disrupts that circuit.
Corticotropin-releasing factor, or CRF, is a hormone released in response to stress. Through a network of brain regions, it drives the brain's reaction to threat, anxiety, and uncertainty. Researchers have long suspected that CRF plays a role in alcohol misuse and relapse, but the precise mechanism has remained elusive.
A new study in mice and rats, published in eLife, maps a specific circuit. CRF-producing neurons in the central amygdala, a brain region that sits at the heart of emotion regulation and the stress response, send direct signals to cholinergic interneurons in the dorsal striatum. That is the brain region involved in habit formation, cognitive flexibility, and behavioral selection. Alcohol suppresses the activation of those interneurons by CRF.
A circuit that overrides habits
The significance lies in what cholinergic interneurons actually do. They act as a kind of brake on automatic behavior, helping the brain override ingrained habits when the situation calls for it. When CRF activates them under stress, the brain can respond more flexibly. When alcohol blocks that activation, the brain falls back on fixed patterns, including learned drinking behavior.
This provides a neurobiological mechanism for something clinicians have recognized for a long time: stress triggers relapse, and alcohol initially reduces tension, but that sense of relief is partly the result of a disrupted neural circuit that should have been keeping impulsive behavior in check.
From circuit to treatment
This is fundamental mechanistic research, and direct clinical applications are not yet on the table. Even so, mapping this particular circuit opens up new directions. If the connection between amygdala CRF neurons and dorsal striatal interneurons is a critical node in the relapse process, it is also a potential target for pharmacological or non-pharmacological interventions.
CRF receptor blockers have previously been tested as a treatment for alcohol use disorder, with mixed results. This study suggests that the location and the circuit at which such an intervention acts may be crucial. Not all CRF signaling is the same, and that distinction could help explain why broad-spectrum antagonists do not always work.