The effects of the protein kinase C (PKC) activator phorbol 12,13-dibutyrate (PDBu) on the ethanol-induced loss of the righting reflex were studied in diabetic and non-diabetic mice. The ethanol-induced loss of the righting reflex was significantly less in diabetic mice than in non-diabetic mice. Intracerebroventricular (i.c.v.) pretreatment with PDBu dose- and time-dependently reduced the ethanol-induced loss of the righting reflex in non-diabetic mice. The reduction of the ethanol-induced loss of the righting reflex caused by PDBu was reversed by concomitant i.c.v. pretreatment with calphostin C, a selective PKC inhibitor. On the other hand, PDBu had no effect on the ethanol-induced loss of the righting reflex in diabetic mice. I.c.v. pretreatment with calphostin C (10 pmol) increased the ethanol-induced loss of the righting reflex in diabetic mice but not in non-diabetic mice. These results suggest that the activation of PKC reduces the ethanol-induced loss of the righting reflex in mice. Furthermore, it is possible that this attenuation of the ethanol-induced loss of the righting reflex in diabetic mice may be due in part to increased PKC activity.