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Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity



Activin receptor signaling, including the transcription factor Smad3, was upregulated in the rat nucleus accumbens (NAc) shell following withdrawal from cocaine. Direct genetic and pharmacological manipulations of this pathway bidirectionally altered cocaine seeking while governing morphological plasticity in NAc neurons. Thus, Activin/Smad3 signaling is induced following withdrawal from cocaine, and such regulation may be a key molecular mechanism underlying behavioral and cellular plasticity in the brain following cocaine self-administration.

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Figure 1: Cocaine self-administration activates Activin receptor/Smad3 signaling.
Figure 2: Manipulating Activin receptor/Smad3 signaling alters drug-related responding.
Figure 3: Smad3 mediates cocaine-induced dendritic spine morphology of neurons in the NAc shell.

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We would like to thank D. Adank for her technical assistance with the self-administration, and J.-X. Li, D. Thorn and J. Siemian for their assistance in conducting the food reinforcement experiments. We thank F. Sim for his technical expertise in microscopy. We thank J.-J. Lebrun (McGill University) for the Smad3 constructs. We acknowledge the assistance of the Confocal Microscope and Flow Cytometry Facility in the School of Medicine and Biomedical Sciences, University at Buffalo. The cocaine used in these experiments was a gift from the National Institute on Drug Abuse. This work was supported by grants R01DA037257 (D.M.D.), NIAAA T-32-AA007583 and GM09545902.

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Authors and Affiliations



A.M.G., Z.-J.W., G.L.S., K.M.B., L.E.M., A.C. and J.A.M. performed behavioral experiments. A.M.G., Z.-J.W., M.S.H. and G.L.S. performed all western blots, mRNA and ChIP experiments. A.M.G. and D.D.-W. conducted dendritic spine experiments. R.L.N. generated and provided HSV constructs. A.M.G., K.C.D. and D.M.D. designed experiments, analyzed data and wrote the manuscript. All of the authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to David M Dietz.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Experimental schematics

(a) Timeline of behavioral testing and location of nucleus accumbens tissue punches. Timeline of behavioral testing for (b) within-session dose-response, (c) drug-induced reinstatement, and (d) food reinforcement experiments.

Supplementary Figure 2 Activin-Receptor/Smad3 signaling in CPu and NAc core

(a) Relative AcvR2a protein expression [t(11) = 0.4485, P = 0.66, n = 6-7/group], and (b) relative ratio of phosphorylated (p) to total Smad3 protein expression [t(12) = 1.501, P = 0.1, n = 6-8/group] in the caudate putamen (CPu) after 7WD. (c) Relative AcvR2a protein expression [t(10) = 2.801, P = 0.01, n = 6/group], and (d) relative ratio of phosphorylated (p) to total Smad3 protein expression [t(8) = 1.001, P = 0.3, n = 5/group] in nucleus accumbens core (NAc core) after 7WD. Data are expressed as mean (± SEM), *P< 0.05 vs. saline.

Supplementary Figure 3 Activin-receptor/Smad3 signaling following acute cocaine or re-exposure to cocaine self-administration

(a) AcvR2a [t(9) = 0.5546, P = 0.59, n = 5-6/group] and (b) p-Smad3/Smad3 [t(9) = 0.4629, P = 0.65, n= 5-6/group] protein expression in the NAc following acute withdrawal to cocaine (1 h after last self-administration session). (c) Timeline of behavioral testing for re-exposure to self-administration. (d) AcvR2a [t(10) = 2.100, P = 0.06, n = 6/group] and (e) p-Smad3/Smad3 [t(9) = 2.745, P = 0.02, n = 5-6/group] protein expression in the NAc following re-exposure to cocaine self-administration following 7 WD. Data are expressed as mean (± SEM), *P< 0.05 vs. saline.

Supplementary Figure 4 Food reinforcement and locomotor activity

Number of reinforcers earned during food reinforcement. There were no differences in the number of reinforcers earned following (a) intra-accumbal microinjections of vehicle, Activin-receptor antagonist (SB-431542, [t(12) = 0.00, P> 0.999, n = 7/group]), (c) Activin A [t(12) = 0.2972, P = 0.7714, n = 7/group], or (e) HSV-GFP, dominant-negative HSV-dnSmad3 or wild-type HSV-Smad3 in the nucleus accumbens [F(2, 19) = 0.5923, P = 0.56, n = 7-8/group]. Total distance traveled in 60 min in a novel environment following either (b) intra-accumbal microinjections of vehicle, Activin-receptor antagonist (SB-431542, [t(12) = 0.4833, P = 0.59, n = 7/group]), (d) Activin A [t(14) = 1.093, P = 0.98, n = 8/group], or (f) HSV-GFP, dominant-negative HSV-dnSmad3 or wild-type HSV-Smad3 in the nucleus accumbens [F(2, 19) = 0.4405, P = 0.65, n = 7-8/group], there were no differences compared to respective controls. Data are expressed as mean (± SEM).

Supplementary Figure 5 In vivo validation of viral-mediated Smad3 overexpression.

(a) Representative Western blots showing phosphorylated (p) and total Smad3 protein levels in the nucleus accumbens of rats following herpes simplex virus-mediated overexpression of dominant-negative (dn) and wild-type (wt) Smad3 constructs, or GFP control. Overexpression of wtSmad3 increased the expression and phosphorylation of Smad3, whereas overexpression of dnSmad3 resulted in a moderate increase in the amount of total Smad3 protein, with no change in the level of phosphorylation. (b) Anatomical placement of viral infection and representative imagesof HSV-infected area in the NAc shell adjacent to the anterior commisure (AC; 4x; scale bar = 100 μm), and medium spiny neuron (20x; scale bar = 50 μm).

Supplementary Figure 6 Full length blots for figure 1 (c&d).

Samples were loaded on a 10% SDS gel and then cut and blotted for Activin-receptor 2a following (a) 1 or (b) 7 d withdrawal from cocaine or saline, or p-Smad3/Smad3 following (c) 1 or (d) 7 d withdrawal from cocaine or saline.

Supplementary Figure 7 Full length blots for supplemental figure 2&3.

Samples were loaded on a 10% SDS gel and then cut and blotted for Activin-receptor 2a and p-Smad3/Smad3 in the (a) CPu or (b) NAc Core following 7 d withdrawal, (c) 1 h after the last self-administration session, or (d) following re-exposure to saline or cocaine self-administration.

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Supplementary Figures 1–7 and Supplementary Tables 1 and 2 (PDF 618 kb)

Supplementary Methods Checklist (PDF 268 kb)

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Gancarz, A., Wang, ZJ., Schroeder, G. et al. Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity. Nat Neurosci 18, 959–961 (2015).

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