Cocaine addiction is a major public health concern with no FDA approved treatment options. Understanding the epigenetic mechanisms that mediate relapse may lead to the development of new therapies. Recent evidence shows that changes to histone post- translational modifications (HPTMs) occur and persist through drug use and abstinence periods. These epigenetic changes alter gene expression, yet the underlying molecular mechanisms remain elusive. Bivalent chromatin domains encompass both gene activating and repressive HPTMs, such as H3K4me3 and H3K27me3, respectively. Expression of the immediate early gene, Nr4a1, is activated immediately following mouse cocaine exposure, and then returns to baseline during abstinence. We hypothesized that Nr4a1 chromatin bivalency regulates transient cocaine-induced Nr4a1 activation, in male and female mouse striatum. Accordingly, we measured mRNA and bivalent HPTMs using sequential chromatin immunoprecipitation in multiple brain regions of the reward pathway following cocaine. We found that cocaine induces a sex-specific effect on Nr4a1 promoter bivalency and corresponding activation in the striatum. As transcription differs between the two major cell types of the striatum, we then sought to investigate bivalency at the cell-type specific level. We established transgenic mouse lines that express an affinity tagged nuclear receptor (GFP-SUN1 fusion) in dopamine D1 receptor- or adenosine A2A receptor-containing cell types. We were able to identify HPTMs at specific gene promoters in these specific cell-types by our hybrid protocol, ICuRuS, that combines INTACT (Isolation of Nuclei Tagged in Specific Cell Types), CUT&RUN (Cleavage Under targets and Release Using Nuclease), and next generation Sequencing. We present data on the protocol optimization as evidence that we successfully established a stream-lined method of cell-type specific quantification of bivalent chromatin. Future studies will apply this methodology to the broader hypothesis that bivalent chromatin plays a prominent role inducing HPTMs and altering persistent gene expression across drug use and abstinence. Taken together, this dissertation presents a novel hybrid method to broadly uncover cell-type specific bivalent promoters and provides mechanistic insights into the sex- and region-specific cocaine regulation of Nr4a1.