BEHAVIORAL EVIDENCE FOR A MODULATING ROLE OF SIGMA-LIGANDS IN MEMORY PROCESSES .2. REVERSION OF CARBON MONOXIDE-INDUCED AMNESIA

This study examined the effect of low doses of a 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 a ligand 1,3-di-(2-tolyl)guanidine (DTG), at doses of 1 to 1000 mu g/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 mu g/kg. The same effect was observed with(+)-N-allylnormetazocine ((+)-SKF 10,047), at doses of 100 to 300 mu g/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. These findings indicate that a, sites may mediate a complete but bell-shaped reversion of CO-induced amnesia. The exact mechanisms remain to be determined, but they may involve the modulation of both the N-methyl-D-aspartate and cholinergic nicotinic systems.