Synchrony between midbrain gene transcription and dopamine terminal regulation is modulated by chronic alcohol drinking

Zahra Z. Farahbakhsh, Katherine M. Holleran, Jonathon P. Sens, Steve C. Fordahl, Madelyn I. Mauterer, Alberto J. López, Verginia C. Cuzon Carlson, Drew D. Kiraly, Kathleen A. Grant, Sara R. Jones and Cody A. Siciliano ()
Additional contact information
Zahra Z. Farahbakhsh: Vanderbilt University
Katherine M. Holleran: Department of Physiology and Pharmacology
Jonathon P. Sens: Department of Physiology and Pharmacology
Steve C. Fordahl: The Department of Nutrition
Madelyn I. Mauterer: Department of Physiology and Pharmacology
Alberto J. López: Vanderbilt University
Verginia C. Cuzon Carlson: Division of Neuroscience
Drew D. Kiraly: Department of Physiology and Pharmacology
Kathleen A. Grant: Division of Neuroscience
Sara R. Jones: Department of Physiology and Pharmacology
Cody A. Siciliano: Vanderbilt University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Alcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. Here, 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods. After the last abstinence period, we paired direct sub-second dopamine monitoring via ex vivo voltammetry in nucleus accumbens core with RNA-sequencing of the ventral tegmental area. We found persistent augmentation of dopamine transporter function, kappa opioid receptor sensitivity, and putative dynorphin release – all inhibitory regulators which act to decrease extracellular dopamine. Surprisingly, though transcript expression was not altered, the relationship between gene expression and functional readouts of these encoded proteins was highly dynamic and altered by drinking history. These results outline the long-lasting synaptic impact of alcohol use and suggest that assessment of transcript-function relationships is critical for the rational design of precision therapeutics.

Date: 2025
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DOI: 10.1038/s41467-025-56715-y

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