The sigma1 (sigma 1) receptor agonists exert potent anti-amnesic effects, as they apparently block the learning impairments either induced by the muscarinic receptor antagonist scopolamine, the N-methyl-D-aspartate receptor antagonist dizocilpine or inherently due to the age-related deficits in senescence-accelerated mice. We recently described the amnesia induced by the beta-amyloid-related peptide beta 25-35, administered centrally in an aggregated form, in mice. The deficits were sensitive to cholinomimetics or to N-methyl-D-aspartate/glycine modulatory site agonists. Herein, we examined the effects of sigma 1 receptor ligands on the beta 25-35 peptide-induced amnesia. The effects of neuro(active) steroids, which interact in vitro and in vivo with sigma 1 receptors were examined in parallel. Mnesic capacity was evaluated seven days after administration of aggregated beta 25-35 peptide (3 nmol), using spontaneous alternation in the Y-maze for spatial short-term memory, or after 14 days, using the step-down type passive avoidance test for long-term memory. The sigma 1 receptor agonists (+)-pentazocine, PRE-084, or SA4503 attenuated, in a dose-dependent and bell-shaped manner, the beta 25-35 peptide-induced deficits on both tests. These effects were antagonized by haloperidol or BMY-14802, confirming the sigma 1 receptor pharmacology. Pregnenolone, dehydroepiandrosterone, and their sulphate esters, but not progesterone, also dose-dependently attenuated the beta 25-35 peptide-induced deficits. Progesterone blocked the beneficial effects of each other neurosteroid, behaving as an antagonist. Furthermore, haloperidol blocked the effects induced by neurosteroids, whereas progesterone antagonized the effects of the non-steroidal sigma 1 receptor agonists, showing a clear crossed pharmacology of different drug classes. These results demonstrate that: (i) the anti-amnesic effect of sigma 1 receptor agonists may be of therapeutic relevance in pathological states affecting the cholinergic and/or glutamatergic systems, such as in pathological aging; (ii) neurosteroids play an important role in learning processes and may collectively constitute a therapeutic target; (iii) the interaction between sigma 1 systems and neurosteroids appears indeed of behavioural relevance.