The attenuation of learning impairments induced after exposure to CO or trimethyltin in mice by sigma (sigma) receptor ligands involves both sigma(1)and sigma(2) sites

1 Sigma (sigma) receptor ligands were previously reported to alleviate lear ning and memory impairments on several pharmacological and pathological rod ent models of amnesia. Such effect was demonstrated as involving the sigma( 1) subtype of sigma receptor. 2 In this study, we characterized the pharmacological effect mediated by si gma ligands on two lesional models of amnesia in mice: (1) the hypoxia-rela ted learning and memory impairment model induced by repeated exposure to ca rbon monoxide (CO) gas; and (2) the intoxication with trimethyltin (1 mg kg (-1)). 3 The selective ol ligand PRE-084 (1 mg kg(-1)) or the non-selective sigma( 1)/sigma(2) compounds DTG (0.1 mg kg(-1)), BD1008 (3 mg kg(-1)), and halope ridol (0.1 mg kg(-1)) reversed significantly the spontaneous alternation de ficits observed 7 days after exposure to CO or 14 days after intoxication w ith trimethyltin. 4 The selective sigma(1) receptor antagonist NE-100 (1 mg kg(-1)) was ineff ective by itself, but blocked completely the PRE-084 effects, partially the DTG effects, and did not affect the effects induced by BD1008 or haloperid ol. 5 A similar pharmacological profile was observed in the step-down type pass ive avoidance test performed 8 days after exposure to CO. 6 These results show that, in contrast to the previously reported amnesia m odels, the impairments induced after exposure to CO or intoxication with tr imethyltin could be alleviated not only by sigma(1) receptor agonists but a lso by sigma(2) agonists. The particular pattern of neurodegeneration obser ved in these lesional models may explain these differences.