The in vivo and in vitro effect of oxiracetam, aniracetam and alpha-glycerylphosphorylcholine (alpha GPC) on protein kinase C (PKC) activity was studied in rat brain cortex and hippocampus. Administration of oxiracetam and alpha GPC in vivo elicited an early increase of particulate histone-directed PKC activity accompanied by a decrease of soluble activity and followed a few hours later by a down regulation of the enzyme. The effect was also observed in vitro when either oxiracetam or alpha GPC were administered at nanomolar concentrations to rat brain cortex slices. Aniracetam had no effect in the cortex but promoted PKC translocation both in vivo and in vitro in the hippocampus. In cortex slices the effect of oxiracetam was antagonized by the addition of AP-5, an NMDA receptor blocker, but not by CNQX and L-AP3, antagonists of AMPA and metabotropic glutamate receptors, respectively. Scopolamine also prevented the increase of particulate PKC elicited by oxiracetam in vitro. In the hippocampus the increase of particulate PKC activity was antagonized by AP-5, CNQX and L-AP3, indicating participation by both ionotropic and metabotropic glutamate receptors in the action of aniracetam. The data support the hypothesis that PKC activation may be a common mechanism amongst cognition stimulating drugs from different chemical classes.