(a) Cocaine self-administration yielded a persistent increase in DNA methylation at a locus within Mctp1 (b) Increased DNA methylation correlated with a concomitant decrease in the expression of Mctp1 (−001 isoform) across treatment groups; F3,26 = 4.07, p<0.05. (c) Cocaine self-administration resulted in a persistent increase in DNA methylation within an intragenic region of Cpeb4. (d) Increased DNA methylation was associated with a long-lasting upregulation of Cpeb4 (001/201 isoform) expression; F3,26 = 5.96, p<0.01. (e) A significant increase in DNA methylation within an intron of Nkain3 was observed after 21 days of abstinence (f) The increase in DNA methylation was associated with a decrease in the expression of Nkain3 (all isoforms) after 21 days of abstinence and relapse testing, but this decrease was not observed when the relapse test did not occur; F3,26 =4.56, p<0.05, naïve vs. IVSA 21 R, p<0.05, IVSA 21 R vs. IVSA 21 NR, p<0.01. Data are displayed as mean ± SEM, all p-values are derived from Holm-Sidak post hoc tests relative to naïve animals, * p<0.05 ** p<0.01.