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Repeated exposure to cocaine produces structural and functional modifications at synapses from neurons in several brain regions including the nucleus accumbens. These changes are thought to underlie cocaine-induced sensitization. The ubiquitin proteasome system plays a crucial role in the remodeling of synapses and has recently been implicated in addiction-related behavior. The ATPase Rpt6 subunit of the 26S proteasome is phosphorylated by Ca2 +/calmodulin-dependent protein kinases II alpha at ser120 which is thought to regulate proteasome activity and distribution in neurons. Here, we demonstrate that Rpt6 phosphorylation is involved in cocaine-induced locomotor sensitization. Cocaine concomitantly increases proteasome activity and Rpt6 S120 phosphorylation in cultured neurons and in various brain regions of wild type mice including the nucleus accumbens and prefrontal cortex. In contrast, cocaine does not increase proteasome activity in Rpt6 phospho-mimetic (ser120Asp) mice. Strikingly, we found a complete absence of cocaine-induced locomotor sensitization in the Rpt6 ser120Asp mice. Together, these findings suggest a critical role for Rpt6 phosphorylation and proteasome function in the regulation cocaine-induced behavioral plasticity.Howell and Gonzales et al. show that the phosphorylation of the 26S proteasome, specifically on the Rpt6 ATPase subunit at serine 120 (S120), to be important for cocaine-induced behavioral plasticity. Cocaine increases Rpt6 S120 phosphorylation and proteasome activity in cultured neurons and in various brain regions of wild type mice including the nucleus accumbens and prefrontal cortex but not in Rpt6 S120D mutant mice in which cocaine-induced locomotor sensitization was completely absent.Cocaine increases Rpt6 S120 phosphorylation and proteasome activity in NAc and PFC.Rpt6 S120D phospho-mimetic mutant lacks cocaine-induced locomotor sensitization.Dopaminergic system linked to cocaine-induced regulation of the proteasome.