Examining the role of E3 Ubiquitin ligase Smurf1 during withdrawal following cocaine self-administration
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Drug addiction is a disease characterized by episodes of relapse despite periods of drug abstinence. The ubiquitin-proteasome system (UPS) degrades proteins and is involved in cocaine-induced plasticity in the nucleus accumbens (NAc); however, E3 ubiquitin ligases (E3s), which conjugates ubiquitin to substrates for proteasomal degradation, have not been studied following cocaine exposure. Here we examined E3 Smad ubiquitinylation regulatory factor-1 (Smurf1) and found that following cocaine self-administration, Smurf1 was decreased, while substrates ras homolog gene family, member A (RhoA) and Smad1/5 were increased, in the NAc in a withdrawal dependent manner. Furthermore, viral-mediated manipulation of Smurf1 bi-directionally mediated cue-induced cocaine seeking but did not affect food seeking or locomotor activity. Finally, Smad1/5-associated transcription factor Runt-related transcript factor 2 (Runx2) was also increased during withdrawal and binding on genes that regulate cocaine plasticity was enhanced. Together, this study demonstrates that Smurf1 mediates relapse behaviour by governing cocaine plasticity during withdrawal following self-administration.