Intrahippocampal administration of (+)-SKF 10,047, a sigma ligand, reverses MK-801-induced impairment of working memory in rats.

In order to clarify the roles of the hippocampal sigma site and phencyclidine (PCP) binding site on the NMDA receptor/channel complex in the regulation of working memory in rats, the effects of intrahippocampal administration of ligands for both binding sites on this behavior were examined with a three-panel runway task. MK-801, a potent noncompetitive NMDA antagonist with high affinity for the PCP site, significantly increased the number of working memory errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), when injected bilaterally at 0.1 and 0.18 microgram/side into the dorsal hippocampus. However, intrahippocampal injection of (+)-SKF 10,047, a sigma ligand, at doses up to 1.0 microgram/side had no significant effect on the number of working memory errors. The working memory impairment induced by intrahippocampal MK-801 (0.18 microgram/side) was attenuated by concurrent injection of 1.0 microgram/side (+)-SKF 10,047, but not by that of 1.0 microgram/side (-)-SKF 10,047. These results suggest that activation of hippocampal sigma and PCP binding sites exerts antagonistic effects on working memory function, possibly through modulation of NMDA receptor-mediated glutamatergic neurotransmission.