Behavioral evidence for a modulating role of sigma ligands in memory processes. II. Reversion of carbon...

This study examined the effect of low doses of sigma ligands on amnesia induced in mice by successive carbon monoxide (CO) exposure. Mice were exposed three consecutive times to CO (10 ml/min, 30-50 s) at 38 degrees C. Spatial working memory impairment was investigated 5 days later by monitoring spontaneous alternation behavior in a Y-maze. Delayed amnesia was examined 7 days after CO exposure by using a step-down passive avoidance test. The preadministration of the sigma ligand 1,3-di-(2-tolyl)guanidine (DTG), at doses of 1 to 1000 microgram/kg, s.c., 30 min before CO exposure did not affect the resulting amnesia in either test. However, when administered 30 min before the test, i.e., 5 or 7 days after CO exposure, this agent completely reversed the CO-induced decrease in alternation performance, at doses of 10 to 100 micrograms/kg. The same effect was observed with (+)-N-allylnormetazocine ((+)-SKF 10,047), at doses of 100 to 300 micrograms/kg, but not with (-)-SKF 10,047. DTG, at the same dose range that reversed the decrease in alternation, also totally reversed the CO-induced decrease in step-down latency in the passive avoidance test. The curve for these effects was bell-shaped; the effects were not observed at the dose of 1 mg/kg. Moreover, alpha-(4-fluorophenyl-2-pyrimidinyl)-1-piperazine butanol (BMY 14802), a putative sigma antagonist (1-10 mg/kg i.p.), did not affect CO-induced amnesia, but when simultaneously administered with DTG, it completely prevented its effect in both tests.(ABSTRACT TRUNCATED AT 250 WORDS)