The potent inhibitory effect of tipepidine on marble-burying behavior in mice

Our previous study revealed that centrally acting non-narcotic antitussives inhibited G-protein-coupled inwardly rectifying K(+) (GIRK) channel currents in brain neurons, and that the tipepidine antitussives had a novel antidepressive-like effect on rats. Furthermore, the antitussives revealed multiplexed ameliorating actions on intractable brain disease models. This study evaluated the therapeutic potential of tipepidine in obsessive-compulsive disorder (OCD) subjects using marble-burying behavior (MBB) tests in mice. In fact, OCD is classified as an anxiety disorder characterized by obsession or compulsion. Although selective 5-HT reuptake inhibitors (SSRIs) are considered first choice agents for the pharmacological treatment of OCD, 50% of patients with OCD failed to respond to SSRIs. The burying of harmless objects such as marbles by mice might reflect the formation of compulsive behavior. The results show that tipepidine reduced MBB in a dose-dependent manner. The effect of tipepidine was significant even at a dosage as small as 5 mg/kg. The tipepidine at 10 mg/kg s.c. nearly abolished MBB without reducing the locomotor activity in mice. It is particularly interesting that the dopamine D₂ antagonist or 5-HT(1A) antagonist partly inhibited the effect of tipepidine on MBB. The results suggest that tipepidine has more of a potent inhibitory effect on MBB, compared with known drugs used for the treatment of OCD, and that the tipepidine action mechanism might differ from that of known drugs.