Possible underlying influence of p38MAPK and NF-κB in the diminished anti-anxiety effect of diazepam in stressed mice.

The present study was designed to explore the possible nitriergic influence and role of p38MAPK and NF-κB in the diminished anti-anxiety effect of diazepam in stressed mice, using the elevated plus maze and light/dark box to assess anxiety. Immobilization stress for 6 h enhanced an anxiety-like behavior and increased plasma nitrite levels in mice. Diazepam (2 mg/kg, i.p.) produced an anti-anxiety effect in unstressed mice, but could not produce any change in anxiety levels of stressed mice. SB-203580 (2 mg/kg, i.p.), a specific inhibitor of p38MAPK, per se produced a significant antianxiety-like activity in stressed mice. Administration of a combination of SB-203580 (2 mg/kg, i.p.) and diazepam (2 mg/kg) in stressed mice produced a significantly higher antianxiety-like activity than that produced by SB-203580 alone. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of the activation of NF-κB, per se produced a significant antianxiety-like activity in stressed mice. Combination of PDTC and diazepam also served to produce a higher significant antianxiety-like activity in stressed mice than that produced by PDTC alone. Diazepam could not produce any change in plasma nitrite levels in both unstressed and stressed mice. Both SB-203580 (2 mg/kg, i.p.) and PDTC (100 mg/kg, i.p.) significantly decreased plasma nitrite levels in stressed mice. The observations indicate that the diminished anti-anxiety effect of diazepam in stressed mice may involve strong nitriergic influence and may further be p38MAPK- and NF-κB-dependent.