TY - JOUR
T1 - E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking
AU - Werner, Craig T.
AU - Viswanathan, Rathipriya
AU - Martin, Jennifer A.
AU - Gobira, Pedro H.
AU - Mitra, Swarup
AU - Thomas, Shruthi A.
AU - Wang, Zi Jun
AU - Liu, Jian Feng
AU - Stewart, Andrew F.
AU - Neve, Rachael L.
AU - Li, Jun Xu
AU - Gancarz, Amy M.
AU - Dietz, David M.
N1 - Funding Information:
This work was supported by the National Institutes of Health (National Institute on Drug Abuse [NIDA] Grant No. R01DA037257 [to DMD], Grant No. S1-R01DA037257 [to DMD], NIDA Grant No. R21DA044486 [to DMD], National Institute of Neurological Disorders and Stroke Grant No. F99NS108543 [to JAM], and National Institute of General Medical Sciences Grant No. R25GM09545902 [to University at Buffalo]). The NIDA Drug Supply Program generously gifted the cocaine used in these studies.
Publisher Copyright:
© 2018 Society of Biological Psychiatry
PY - 2018/12/15
Y1 - 2018/12/15
N2 - Background: Substance use disorder is a neurobiological disease characterized by episodes of relapse despite periods of withdrawal. It is thought that neuroadaptations in discrete brain areas of the reward pathway, including the nucleus accumbens, underlie these aberrant behaviors. The ubiquitin–proteasome system degrades proteins and has been shown to be involved in cocaine-induced plasticity, but the role of E3 ubiquitin ligases, which conjugate ubiquitin to substrates, is unknown. Here, we examined E3 ubiquitin-protein ligase SMURF1 (SMURF1) in neuroadaptations and relapse behavior during withdrawal following cocaine self-administration. Methods: SMURF1 and downstream targets ras homolog gene family, member A (RhoA), SMAD1/5, and Runt-related transcript factor 2 were examined using Western blotting (n = 9–11/group), quantitative polymerase chain reaction (n = 6–9/group), co-immunoprecipitation (n = 9–11/group), tandem ubiquitin binding entities affinity purification (n = 5–6/group), and quantitative chromatin immunoprecipitation (n = 3–6/group) (2 rats/sample). Viral-mediated gene transfer (n = 7–12/group) and intra-accumbal microinjections (n = 9–10/group) were used to examine causal roles of SMURF1 and substrate RhoA, respectively, in cue-induced cocaine seeking. Results: SMURF1 protein expression was decreased, while SMURF1 substrates RhoA and SMAD1/5 were increased, in the nucleus accumbens on withdrawal day 7, but not on withdrawal day 1, following cocaine self-administration. Viral-mediated gene transfer of Smurf1 or constitutive activation of RhoA attenuated cue-induced cocaine seeking, while catalytically inactive Smurf1 enhanced cocaine seeking. Furthermore, SMURF1-regulated, SMAD1/5-associated transcription factor Runt-related transcript factor 2 displayed increased binding at promoter regions of genes previously associated with cocaine-induced plasticity. Conclusions: SMURF1 is a key mediator of neuroadaptations in the nucleus accumbens following cocaine exposure and mediates cue-induced cocaine seeking during withdrawal.
AB - Background: Substance use disorder is a neurobiological disease characterized by episodes of relapse despite periods of withdrawal. It is thought that neuroadaptations in discrete brain areas of the reward pathway, including the nucleus accumbens, underlie these aberrant behaviors. The ubiquitin–proteasome system degrades proteins and has been shown to be involved in cocaine-induced plasticity, but the role of E3 ubiquitin ligases, which conjugate ubiquitin to substrates, is unknown. Here, we examined E3 ubiquitin-protein ligase SMURF1 (SMURF1) in neuroadaptations and relapse behavior during withdrawal following cocaine self-administration. Methods: SMURF1 and downstream targets ras homolog gene family, member A (RhoA), SMAD1/5, and Runt-related transcript factor 2 were examined using Western blotting (n = 9–11/group), quantitative polymerase chain reaction (n = 6–9/group), co-immunoprecipitation (n = 9–11/group), tandem ubiquitin binding entities affinity purification (n = 5–6/group), and quantitative chromatin immunoprecipitation (n = 3–6/group) (2 rats/sample). Viral-mediated gene transfer (n = 7–12/group) and intra-accumbal microinjections (n = 9–10/group) were used to examine causal roles of SMURF1 and substrate RhoA, respectively, in cue-induced cocaine seeking. Results: SMURF1 protein expression was decreased, while SMURF1 substrates RhoA and SMAD1/5 were increased, in the nucleus accumbens on withdrawal day 7, but not on withdrawal day 1, following cocaine self-administration. Viral-mediated gene transfer of Smurf1 or constitutive activation of RhoA attenuated cue-induced cocaine seeking, while catalytically inactive Smurf1 enhanced cocaine seeking. Furthermore, SMURF1-regulated, SMAD1/5-associated transcription factor Runt-related transcript factor 2 displayed increased binding at promoter regions of genes previously associated with cocaine-induced plasticity. Conclusions: SMURF1 is a key mediator of neuroadaptations in the nucleus accumbens following cocaine exposure and mediates cue-induced cocaine seeking during withdrawal.
KW - Cocaine
KW - Cue-induced cocaine seeking
KW - E3 ubiquitin ligase
KW - Nucleus accumbens
KW - Substance use disorder
KW - Ubiquitin–proteasome system
UR - http://www.scopus.com/inward/record.url?scp=85054168600&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2018.07.013
DO - 10.1016/j.biopsych.2018.07.013
M3 - Article
C2 - 30158054
AN - SCOPUS:85054168600
SN - 0006-3223
VL - 84
SP - 881
EP - 892
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 12
ER -