MDMA (3,4-methylenedioxy-N-methamphetamine) as an empathogenic drug causes neurotoxicity although the mechanisms have not been fully elucidated. The A2a adenosine receptor modulates the reinforcement efficacy and neurotoxicity of MDMA. A2a receptor activation inhibits Nuclear Factor-Kappa B (NF-${kappa}B$) activation and nuclear translocation by a known mechanism. In the present study, we aimed to compare the NF-${kappa}B$ activity level in rat hippocampus between two doses of MDMA exposure (10 and 20 mg/kg) using either A2aR agonist (CGS) or A2aR antagonist (SCH). Adult male Sprague-Dawley rats were subjected to MDMA followed by intraperitoneal CGS (0.03 mg/kg) or SCH (0.03 mg/kg) injection. The hippocampi were then removed for western blot and RT-PCR analyses. Administration of MDMA dose-dependently increased the expression of NF-${kappa}B$ both at mRNA and protein levels. We also found that administration of CGS following MDMA significantly increased the NF-${kappa}B$ expression especially in MDMA 20+CGS group. By contrast, administration of the A2a-R antagonist SCH resulted in a dose-dependent decrease in NF-${kappa}B$ mRNA and protein. Our study results revealed that MDMA has powerful detrimental effects on expression of NF-${kappa}B$ in a dose-dependent manner. On the other hand, co-administration of A2a agonist (CGS) can protect against MDMA neurotoxic effects by increasing NF-${kappa}B$ expression levels; suggesting a potential application for protection against the neurotoxic effects observed in MDMA users.