Ameliorating effects of sigma receptor ligands on the impairment of passive avoidance tasks in mice: involvement in the central acetylcholinergic system.

Three sigma receptor ligands were examined for their ameliorating effects on p-chloroamphetamine-induced amnesia in mice. p-Chloroamphetamine was administered intraperitoneally 30 min before the training session of the passive avoidance response. Each sigma receptor ligand was administered 60 min before or immediately after the training session, or 60 min before the retention test. (+)-N-Allylnormetazocine ((+)-SKF-10,047), a prototype benzomorphan sigma receptor ligand, significantly reduced the p-chloroamphetamine-induced amnesia in these three administration schedules, as do acetylcholinesterase inhibitors. On the contrary, the significant anti-amnesic effects elicited by non-benzomorphan sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) or (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperizine ((+)-3-PPP), were observed depending upon the timing of their administration. In addition, the ameliorating effect of (+)-SKF-10,047 against the p-chloroamphetamine-induced amnesia was superior to that of (-)-SKF-10,047. The (+)-SKF-10,047-induced anti-amnesic effect was significantly antagonized by the concurrent administration of either scopolamine, a muscarinic receptor antagonist, or hemicholinium-3, an inhibitor of the Na(+)-dependent high-affinity choline uptake site. These findings indicated that sigma receptor ligands had anti-amnesic effects against drug-induced memory impairment. In addition, the anti-amnesic effect of (+)-SKF-10,047 was superior to those of other sigma receptor ligands, and was mediated by both the sigma receptor and the central acetylcholinergic system.