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Cocaine addiction is a major health issue with no FDA-approved medication, so novel therapeutic target identification is necessary. Recent technological advances provide novel target identification using large-scale discovery-based quantification of the proteome in response to cocaine. This approach improves upon historically utilized methods as proteins are quantified regardless of whether the protein is regulated by the manipulation. Additionally, it avoids experimenter biases and assumptions and reduces labor and cost requirements. In this chapter we discuss proteome-wide effects of cocaine in the nucleus accumbens in rats that self-administered cocaine or saline, a paradigm with excellent reproducibility and strong validity as a model of drug-taking and -seeking behavior. Also discussed are the proteomic effects of environmental enrichment, which provides a unique opportunity for novel target identification …