Effect of active fragments of arginine-vasopressin on the disturbance of spatial cognition in rats

The effect of arginine(8)-vasopressin (AVP(1-9)) and its metabolite C-terminal fragments on the scopolamine-induced disruption of spatial cognition were investigated using an 8-arm radial maze task in rats. AVP(1-9), (10 mu g/kg s.c.) markedly improved the disruption of spatial cognition by treatment with scopolamine (0.5 mg/kg i.p.), and 60% of the rats recovered to a normal level. The main metabolite of AVP(1-9), AVP(4-9) (0.5 and 1 ng/kg s.c.) also significantly improved the scopolamine-induced deficit of spatial memory. The activity of AVP(4-9) was determined to be about 10000 fold greater than that of AVP(1-9). An intracerebroventricular (i.c.v.) injection of 10 fg of AVP(5-8), however, showed a lower activity. Both AVP(6-8), and AVP(5-7), which are both metabolites of AVP(5-8), demonstrated no activity. The scopolamine-induced disruption of spatial memory was found to improve after a microinjection of AVP(4-9) (1 fg) into the ventral hippocampus (VH) region, but not into the dorsal hippocampus (DH). In an in vivo microdialysis study, the scopolamine-induced acetylcholine (ACh) release from the VH was slightly potentiated by treatment with AVP(4-9) (10 fg i.c.v.). In addition, an AVP(4-9) analogue, No. 302, which is a synthetic hexapeptide and has a longer half-life, also demonstrated a markedly improved effect, which had a 10-fold higher activity than that with AVP(4-9). AVP(4-9) is the most potent activity of all the endogenous metabolites of the AVP(1-9) and the new synthetic AVP(4-9) analogue, No. 302 (obtained from Nippon Chemiphar Co.), substituting Ser for Cys-Cys in hexapeptide, has higher activity than that of AVP(4-9). These results indicated [Ser(6)] hexapeptide has an important role in behavioral activity. Based on these results, it is possible that AVP(1-9) and its metabolite AVP(4-9) could, thus, be useful in treating cholinergic dysfunction diseases, such as Alzheimer's disease. Hexapeptide may play an important role in improving the spatial memory by promoting the release of ACh in the VH region.