Inhibition of hyperpolarization-activated cation currents by phencyclidine and some sigma ligands in rat hippocampal CA1 pyramidal neurons in vitro

Abstract

Using whole-cell voltage-clamp recordings, hyperpolarization-activated cation currents ( I h) were elicited with hyperpolarizing voltage jumps in CA1 pyramidal neurons of rat hippocampal slices, and the effects of phencyclidine (PCP) and some sigma ligands on I h were studied. PCP concentration-dependently (0.1–100 μM) suppressed I h and shifted the activation curve of I h to the negative direction. d-3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 20 μM) and MK-801 (30 μM), competitive and non-competitive NMDA blockers, respectively, failed to mimic the inhibitory effect of PCP on I h, and suppression of I h by PCP was unaffected in the presence of these blockers. To explore the involvement of sigma 1 receptors in the reduction of I h, the effects of representative sigma 1 ligands were studied. SKF10047 (100 μM), a sigma 1 agonist, attenuated the maximal I h and shifted the half-activation potential of I h to the hyperpolarized direction. In the presence of the sigma 1 antagonist NE-100 (1 μM), which alone did not affect I h, the effect of SKF10047 on I h was unaltered. By contrast, a higher concentration of NE-100 (10 μM) mimicked the effect of SKF10047. Again, no antagonism of I h suppression by SKF10047 was obtained with rimcazole (100 μM), a sigma 1 receptor antagonist that is structurally distinct from NE-100. This concentration of rimcazole alone resulted in a slight but significant reduction of I h. Thus these major sigama 1 ligands appear to suppress I h independently of their agonistic or antagonistic properties. The results of this study suggest that PCP and some sigma ligands could modulate cell excitability partly through their action on I h.