Editors' ChoiceNeuroscience

Addiction by Activin

Sci. Signal.  21 Jul 2015:
Vol. 8, Issue 386, pp. ec196
DOI: 10.1126/scisignal.aad0323

Drugs of abuse alter neuronal function and circuits in ways that contribute to addiction and relapse. The nucleus accumbens (NAc) is a region of the brain that is associated with cocaine addiction. Activins are members of the transforming growth factor–β family (TGF-β) and regulate cell fate in various cell types, including neurons. Gancarz et al. found that a week of withdrawal after a period of cocaine self-administration in rats increased the abundance of Activin receptor 2a (ACVR2a) and phosphorylation of its downstream mediator, the transcription factor SMAD3, specifically in NAc neurons. Both ACVR2a abundance and SMAD3 phosphorylation remained increased after reexposure to cocaine after withdrawal. Cocaine reinstatement after withdrawal increased the density of dendritic spines on NAc medium spiny neurons (MSN). Intra-accumbal injection of Activin A increased cocaine self-administration after withdrawal in rats, whereas injection of Activin receptor antagonist SB-43152 decreased self-administration. Compared with rats transduced with a control virus, rats transduced with a virus containing wild-type SMAD3 had both increased cocaine self-administration after cocaine reinstatement following withdrawal and increased MSN spine density, whereas those transduced with a virus containing a dominant-negative mutant of SMAD3 had decreased cocaine self-administration after reinstatement and decreased MSN spine density. Food-seeking behavior was unaffected by pharmacological modulation of Activin signaling or altering SMAD3 abundance, suggesting a specific effect of Activin-SMAD3 signaling on behaviors associated with drug addiction. Chromatin immunoprecipitation assays showed that SMAD3 binding to target genes associated with actin dynamics and cocaine-induced neuronal plasticity increased in NAc neurons after cocaine withdrawal. The findings reveal a mechanism by which cocaine alters the activity and morphology of NAc neurons.

A. M. Gancarz, Z.-J. Wang, G. L. Schroeder, D. Damez-Werno, K. M. Braunscheidel, L. E. Mueller, M. S. Humby, A. Caccamise, J. A. Martin, K. C. Dietz, R. L. Neve, D. M. Dietz, Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity. Nat. Neurosci. 18, 959–961 (2015). [PubMed]