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Nat Commun. 2019 Sep 12;10(1):4140. doi: 10.1038/s41467-019-12122-8.

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

Author information

1
Department of Pharmacology and Toxicology, Program in Neuroscience, Research Institute on Addictions, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.
2
Department of Physiology and Biophysics, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.
3
Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
4
Department of Psychology, California State University Bakersfield, Bakersfield, CA, 93311, USA.
5
Gene Delivery Technology Core, Massachusetts General Hospital, Cambridge, MA, 02139, USA.
6
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
7
Department of Pharmacology and Toxicology, Program in Neuroscience, Research Institute on Addictions, The State University of New York at Buffalo, Buffalo, NY, 14214, USA. ddietz@buffalo.edu.
8
Department of Psychology, The State University of New York at Buffalo, Buffalo, NY, 14214, USA. ddietz@buffalo.edu.

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.

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