Already moderate alcohol consumption has detrimental long-term effects on brain function. However, how alcohol produces its potent addictive effects despite being a weak reinforcer is a poorly understood conundrum that likely hampers the development of successful interventions to limit heavy drinking. In this translational study, we demonstrate widespread increased mean diffusivity in the brain gray matter of chronically drinking humans and rats. These alterations appear soon after drinking initiation in rats, persist into early abstinence in both species, and are associated with a robust decrease in extracellular space tortuosity explained by a microglial reaction. Mathematical modeling of the diffusivity changes unveils an increased spatial reach of extrasynaptically released transmitters like dopamine that may contribute to alcohol's progressively enhanced addictive potency.

Center for Biomaterials and Tissue Engineering Universitat Politècnica de València Valencia Spain

Charles University 2nd Faculty of Medicine 150 06 Prague 5 Czech Republic

Department of Addiction Medicine Central Institute of Mental Health University of Heidelberg 68159 Mannheim Germany

Department of Clinical Psychology Central Institute of Mental Health University of Heidelberg 68159 Mannheim Germany

Department of Psychopharmacology Central Institute of Mental Health University of Heidelberg 68159 Mannheim Germany

Institute of Experimental Medicine AS CR 142 20 Prague 4 Czech Republic

Institute of Neuroimmunology Slovak Academy of Sciences Bratislava Slovakia

Instituto de Neurociencias Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández Sant Joan d'Alacant Spain

School of Pharmacy University of Camerino Camerino Italy

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