A novel role for the actin-binding protein drebrin in regulating opiate addiction

Jennifer A. Martin, Craig T. Werner, Swarup Mitra, Ping Zhong, Zi-Jun Wang, Pedro H. Gobira, Andrew. F. Stewart, Jay Zhang, Kyra Erias, Justin N. Siemian, Devin Hagarty, Lauren E. Mueller, Rachael L. Neve, Jun-Xu Li, Ramesh Chandra, Karen C. Dietz, Mary Kay Lobo, Amy M. Gancarz, Zhen Yan and David M. Dietz ()
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Jennifer A. Martin: The State University of New York at Buffalo
Craig T. Werner: The State University of New York at Buffalo
Swarup Mitra: The State University of New York at Buffalo
Ping Zhong: The State University of New York at Buffalo
Zi-Jun Wang: The State University of New York at Buffalo
Pedro H. Gobira: The State University of New York at Buffalo
Andrew. F. Stewart: The State University of New York at Buffalo
Jay Zhang: The State University of New York at Buffalo
Kyra Erias: The State University of New York at Buffalo
Justin N. Siemian: The State University of New York at Buffalo
Devin Hagarty: California State University Bakersfield
Lauren E. Mueller: The State University of New York at Buffalo
Rachael L. Neve: Gene Delivery Technology Core, Massachusetts General Hospital
Jun-Xu Li: The State University of New York at Buffalo
Ramesh Chandra: University of Maryland School of Medicine
Karen C. Dietz: The State University of New York at Buffalo
Mary Kay Lobo: University of Maryland School of Medicine
Amy M. Gancarz: California State University Bakersfield
Zhen Yan: The State University of New York at Buffalo
David M. Dietz: The State University of New York at Buffalo

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1+ subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.

Date: 2019
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DOI: 10.1038/s41467-019-12122-8

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