Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, activates Toll-like receptors (TLRs). Porphyromonas gingivalis (Pg) appears to play a role in the development of periodontal disease. In vitro studies have suggested that unlike LPS derived from Escherichia coli (Ec-LPS), which stimulates TLR4, LPS derived from Pg (Pg-LPS) may inhibit the TLR4. Mice exposed to a novel environment show hyperlocomotion that is inhibited by systemic administration of Ec-LPS. However, whether Pg-LPS influences novelty-induced locomotion is unknown. Therefore, we carried out an open field test to analyze the effects of Pg-LPS. For comparison, effects of Ec-LPS were also studied. Male ddY mouse (25-30 g) were used. The movement of each mouse in the open field was recorded for 30 min using a commercially available behavioural analysis system and the distance travelled (cm) was determined. Each compound was given intraperitoneally 4h before the open field test. Ec-LPS 500 and 840 µg/kg, but not 100 µg/kg, inhibited novelty-induced increases in distance travelled. Inhibition of hyperlocomotion by 840 µg/kg Ec-LPS was counteracted by co-administration of the TLR4 antagonist TAK-242 (3.0 mg/kg). Pg-LPS (100, 500 or 840 µg/kg) failed to alter novelty-induced locomotion. The present results provide in vivo evidence that Ec- and Pg-LPS induce different effects. Thus, Ec- but not Pg-LPS inhibits novelty-induced locomotor activity in mice by activating TLR4.