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.