The attenuation of learning impairments induced after exposure to CO or trimethyltin in mice by sigma (σ) receptor ligands involves both σ₁ and σ₂ sites

1. Sigma (σ) receptor ligands were previously reported to alleviate learning and memory impairments on several pharmacological and pathological rodent models of amnesia. Such effect was demonstrated as involving the σ₁ subtype of σ receptor. 2. In this study, we characterized the pharmacological effect mediated by a ligands on two lesional models of amnesia in mice: (1) the hypoxia-related learning and memory impairment model induced by repeated exposure to carbon monoxide (CO) gas; and (2) the intoxication with trimethyltin (1 mg kg^-1). 3. The selective σ₁ ligand PRE-084 (1 mg kg^-1) or the non-selective σ₁/σ₂ compounds DTG (0.1 mg kg^-1), BD1008 (3 mg kg^-1), and haloperidol (0.1 mg kg^-1) reversed significantly the spontaneous alternation deficits observed 7 days after exposure to CO or 14 days after intoxication with trimethyltin. 4. The selective σ₁ receptor antagonist NE-100 (1 mg kg^-1) was ineffective by itself, but blocked completely the PRE-084 effects, partially the DTG effects, and did not affect the effects induced by BD1008 or haloperidol. 5. A similar pharmacological profile was observed in the step-down type passive avoidance test performed 8 days after exposure to CO. 6. These results show that, in contrast to the previously reported amnesia models, the impairments induced after exposure to CO or intoxication with trimethyltin could be alleviated not only by σ₁ receptor agonists but also by σ₂ agonists. The particular pattern of neurodegeneration observed in these lesional models may explain these differences.