Ameliorative effect of NC-1900, a new AVP_4-9 analog, through vasopressin V_1A receptor on scopolamine-induced impairments of spatial memory in the eight-arm radial maze

The mechanism by which NC-1900, a new pGlu-Asn-Cys(Cys)-Pro-Arg-Gly-NH₂ (AVP_4-9) analog, improves spatial memory in rats using an eight-arm radial maze was examined. Even at very low doses (0.2 ng/kg for s.c., 1 μg/kg for p.o., 1 fg for i.c.v.) NC-1900 improved scopolamine-induced impairment of spatial memory. NC-1900 (1 ng/kg, s.c.) also improved impairment of spatial memory induced by pirenzepine, a muscarinic₁ (M₁) receptor antagonist, and by KN-62, a Ca²⁺/calmodulin (CaM)-dependent protein kinase II inhibitor. [Pmp¹, Tyr(Me)²]-Arg⁸-vasopressin, a vasopressin_1A (V_1A) receptor antagonist, and nicardipine, L-type Ca²⁺ blocker, but not OPC-31260, a V₂ antagonist, suppressed the effect of NC-1900 on scopolamine-induced impairment of spatial memory. A microdialysis study showed that NC-1900 did not affect acetylcholine release in the ventral hippocampus (VH) of intact rats or of scopolamine-treated rats. NC-1900 (1 μM) increased [Ca²⁺]_i in the VH than in the dorsal hippocampus (DH). Pretreatment with nicardipine (1 μM) and Ca²⁺-free conditions inhibited the NC-1900-induced [Ca²⁺]_i response in the VH. Whereas co-administration of NC-1900 (1 μM) and carbachol (500 μM) increased [Ca²⁺]_i in the VH. Moreover, nicardipine concentration-dependently inhibited the increase in [Ca²⁺]_i induced by the co-administration of NC-1900 and carbachol in the VH. These results suggest that NC-1900 activates the V_1A receptor at the postsynaptic cholinergic nerve, and causes a transient influx of intracellular Ca²⁺ through L-type Ca²⁺ channels, to interact with the M₁ receptor. The activation of these Ca²⁺-dependent processes induced by NC-1900 may be involved in the positive effect of NC-1900 on scopolamine-induced impairment of spatial memory.