This study was designed to explore the effect of P2X7 receptor (P2X7R) activation on the expression of p38 MAP kinase (p38 MAPK) enzyme in hippocampal slices of wild-type (WT) and P2X7R(-/-) mice using the Western blot technique and to clarify its role in P2X7 receptor mediated [(3)H]glutamate release. ATP (1 mM) and the P2X7R agonist BzATP (100 microM) significantly increased p38 MAPK phosphorylation in WT mice, and these effects were absent in the hippocampal slices of P2X7R(-/-) mice. Both ATP- and BzATP-induced p38 MAPK phosphorylations were sensitive to the p38 MAP kinase inhibitor, SB203580 (1 microM). ATP elicited [(3)H]glutamate release from hippocampal slices, which was significantly attenuated by SB203580 (1 microM) but not by the extracellular signal-regulated kinase (ERK1/2) inhibitor, PD098095 (10 microM). Consequently, we suggest that P2X7Rs and p38 MAPK are involved in the stimulatory effect of ATP on glutamate release in the hippocampal slices of WT mice.