Study Links Brain Receptor Changes in Dorsomedial Striatum to Compulsive Alcohol Drinking Despite Negative Consequences
A new preclinical study found that calcium-permeable AMPA receptors (CP-AMPARs) in the dorsomedial striatum (DMS) undergo compositional and functional changes as mice develop aversion-resistant alcohol drinking (ARD). The DMS is a brain region associated with goal-directed behavior, and leading theories suggest compulsive drug use involves a shift away from DMS control toward habitual, dorsolateral striatum-driven behavior. These findings suggest that repeated alcohol binges progressively alter DMS glutamate signaling in ways that may underlie the hallmark feature of alcohol use disorder: drinking despite known negative consequences.
Researchers used western blotting, microinjections, and ex-vivo electrophysiology in a mouse model to examine how AMPA receptor (AMPAR) subunit composition and function in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) change during the development of aversion-resistant alcohol drinking (ARD), defined as continued drinking despite quinine adulteration. In aversion-sensitive mice, DMS GluA1 levels were negatively associated with quinine-adulterated alcohol consumption, while ARD mice showed positive relationships between GluA1/GluA2 ratios in both the DMS and DLS and drinking levels. Electrophysiological recordings of DMS spiny projection neurons (SPNs) revealed a greater rectification index in ARD mice compared to aversion-sensitive mice, indicating increased CP-AMPAR expression following ARD development. Paradoxically, pharmacological blockade of DMS CP-AMPARs increased quinine-adulterated drinking, suggesting that CP-AMPAR activity in the DMS initially serves a protective, aversion-encoding function. Taken together, the findings indicate that early DMS CP-AMPAR activity helps suppress compulsive drinking, but repeated alcohol binges recruit these receptors in a way that ultimately contributes to the loss of aversion sensitivity characteristic of alcohol use disorder.
What's missing
As a preprint on bioRxiv, this study has not yet undergone formal peer review, and its findings should be interpreted with caution. The study is conducted entirely in mice, and it is unclear how well the quinine-adulteration model of aversion-resistant drinking translates to human alcohol use disorder. The paper does not address whether the observed CP-AMPAR changes are reversible with abstinence or pharmacological intervention, nor does it clarify the precise causal mechanism linking increased CP-AMPAR recruitment to the loss of aversion sensitivity.
What different sources said
- bioRxivCenter
Dorsomedial Striatum Calcium Permeable AMPA Receptors in the Development of Aversion-Resistant Alcohol Drinking
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