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We examined the effect of lidocaine on phosphorylation of the tyrosine kinase focal adhesion kinase (PP125FAK) in rat hippocampal slices by immunoblotting with both antiphosphotyrosine and specific anti-PP125FAK antibodies in the presence of tetrodotoxin (1 μM). Lidocaine induced a concentration-related increase in tyrosine phosphorylation of the 125-kDa band corresponding to PP125FAK phosphorylation (EC50 value=0.39±0.09 μM, maximal effect=169±28% of control, P<0.001). This effect was sensitive to neither the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK 801, 10 μM) nor the inhibitor of the ryanodine receptor dantrolene (30 μM). In contrast, it was completely blocked by the protein kinase C (PKC) inhibitors chelerythrin, bisindolylmaleimide I (GF 109203X) and bisindolylmaleimide IX (RO-318220, 10 μM). We conclude that lidocaine increases phosphorylation of the tyrosine kinase PP125FAK in the rat hippocampus by a tetrotoxin (TTX)-insensitive mechanism which involves activation of PKC. [Copyright &y& Elsevier]