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

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 mu M) suppressed I-h and shifted the activation curve of I-h to the negative direction. D-3-(2-Carboxypipcrazin-4-yl)-propyl-1-phosphonic acid (CPP, 20 mu M) and MK-801 (30 mu M), competitive and non-competitive NMDA blockers, respectively, failed to mimic the inhibitory effect of PCP on Ih, and suppression of I-h by PCP was unaffected in the presence of these blockers. To explore the involvement of sigma, receptors in the reduction of I-h, the effects of representative sigma, ligands were studied. SKF10047 (100 mu M), a sigma, 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, antagonist NE-100 (1 mu M), 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 mu M) mimicked the effect of SKF10047. Again, no antagonism of I-h suppression by SKF10047 was obtained with rimcazole (100 mu M), a sigma, 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. (C) 2007 Elsevier Ltd. All rights reserved.