Electrophysiological changes in rat hippocampal pyramidal neurons produced by cholecystokinin octapeptide.

Effects of cholecystokinin octapeptide (CCK-8) were investigated in CA1 pyramidal neurons of rat hippocampal slice cultures using the whole-cell patch-clamp technique. In the current-clamp mode, CCK-8 (100 nM) produced slight depolarizaton (2.1 +/- 0.3 mV) and reduced the amplitude of afterhyperpolarization following a train of spikes. CCK-8 (10 nM-1 microM) concentration-dependently reduced the amplitude of afterhyperpolarization. CCK-4, a selective agonist for CCK(B) receptors, also attenuated the amplitude of afterhyperpolarization. CCK-8-induced suppression was completely abolished by (+)L-365,260, a selective CCK(B) receptor antagonist, but not by (-)L-364,718, a selective CCK(A) receptor antagonist. Similarly, CCK-8 reduced the tail currents following a depolarizing pulse. The tail currents were characterized as Ca2+-activated K+ currents. When neurons were held at a holding potential of -40 mV, CCK-8 elicited inward currents with a reduction of membrane conductance. This current had a relatively linear current voltage relationship and was reversed in polarity at membrane potentials close to the K+ equilibrium potential, suggesting that CCK-8 decreases leak K+ currents. Moreover, voltage-activated Ca2+ currents were partially blocked by CCK-8, and this effect was enhanced by intracellular application of GTPgammaS (300 microM) or a protein phosphatase inhibitor, okadaic acid (100 nM), and attenuated by GDPbetaS (300 microM) or a protein kinase inhibitor, staurosporin (400 nM). In acutely-prepared hippocampal slices from neonatal rats, CCK-8 also depolarized CA1 pyramidal neurons and suppressed afterhyperpolarization following a train of action potentials. These results indicate that CCK-8 increases neuronal excitability by suppressing leak K+ currents and Ca2+-activated K+ currents in CA1 pyramidal neurons of the hippocampus through activation of CCK(B) receptors.