Propofol has been demonstrated as a drug of abuse in humans. Our previous study indicated that dexamethasone, a potent agonist of glucocorticoid receptor (GR), inhibited propofol-maintained rat self-administration behaviors by systematic injection. However, the direct effect of GR in the nucleus accumbens (NAc) on propofol self-administration behavior has not been explored. The propofol-maintained self-administration was established in rats after a successive 3-h daily self-administration of propofol for 14days. On day 15, 30min prior to the last training, rats received one of three doses (0.3, 1.0, or 3.0μg/site) of dexamethasone or vehicle via intra-NAc injection. The number of active nose-poke responses, propofol injections, and inactive nose-poke responses was recorded. Dopamine D1 receptor and c-Fos expressions were detected. Plasma corticosterone level was measured by enzyme-linked immunosorbent assay. Intra-NAc administration of dexamethasone (1.0 and 3.0μg/site) facilitated the active nose-poke responses, which was accompanied by the upregulation of D1 receptor and c-Fos in the NAc. Plasma corticosterone level was not changed in dexamethasone-treated groups. This study provides crucial evidence that GR in the NAc plays an important role in regulating propofol self-administration behaviors in rats, which may be mediated by changes in D1 receptor and c-Fos expressions, and this also needs further examination with GR antagonist in the future.