VINCONATE, A COGNITIVE ENHANCER, AND PI TURNOVER PHOSPHOLIPASE-C SYSTEMS IN THE BRAIN

The molecular mechanisms for the stimulation of inositol 1-phosphate ( IP1) formation by vinconate were investigated using preparations of ra t brain. Vinconate (10(-8)-10(-3) M) dose-dependently inhibited the bi nding of [H-3]quinuclidinyl benzilate ([H-3]QNB) to muscarinic acetylc holine receptors and its IC50 value for [H-3]QNB binding was 1.7 x 10( -5) M. The rightward shift of carbachol displacement curve of [H-3]QNB binding by GTP (10(-4) M) was completely abolished by vinconate (10(- 5) M). Carbachol (10(-8)-10(-2) M) increased [H-3]IP1 formation in a d ose-dependent manner and the carbachol-induced [H-3]IP1, formation was significantly accentuated by vinconate (10(-5) M). The enhancement of [H-3]IP1 accumulation by vinconate was inhibited by approximately 50% in the presence of atropine (10(-5) M), although phentolamine and ket anserin had no effects on the stimulatory effect of vinconate on [H-3] IP1 formation. Vinconate showed no alteration in the binding of [H-3]g uanosine 5'-(beta,gamma-imino)triphosphate [H-3]Gpp(NH)p) to the crude synaptic membranes. The enhancement of phosphatidylinositol 4,5-bipho sphate (PIP2)-specific phospholipase C (PLC) activity by GTP was unaff ected in the presence of 10(-3) M vinconate, whereas vinconate alone d ose-dependently enhanced the activities of both PIP2-specific and cyto solic PLC. These results suggest that vinconate may induce the facilit ation of phosphatidylinositide (PI) turnover via the stimulation of mu scarinic acetylcholine receptors, the enhancement of coupling between muscarinic acetylcholine receptors and GTP-binding protein, and the di rect activations of PIP2-specific and cytosolic PLC.