Cognitive and Histopathological Alterations in Rat Models of Early- and Late-Phase Memory Dysfunction: Effects of Sigma-1 Receptor Activation

Background: Sigma-1 receptors are highly expressed in brain areas related to cognitive function and are a promising target for anti-amnesic treatments. We previously showed that activation of sigma-1 receptors by the selective agonist compound methyl(1 R,2 S/1 S,2 R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropane carboxylate [(+/-)- +/- )- PPCC] promotes a remarkable recovery in rat models of memory loss associated to cholinergic dysfunction. Objective: In this study, we sought to assess the role of (+/-)-PPCC +/- )-PPCC on working memory deficits caused by noradrenergic depletion. Methods: Animals with a mild or severe working memory deficits associated to varying degrees of noradrenergic neuronal depletion were treated with the sigma-1 agonist just prior to the beginning of each behavioral testing session. Results: While (+/-)-PPCC +/- )-PPCC alone at a dose of 1 mg/kg/day failed to affect working memory in lesioned animals, its association with the alpha(2) adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (+/-)-PPCC +/- )-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation. Conclusions: Future studies are thus necessary to address the effects of long-lasting (+/-)-PPCC +/- )-PPCC treatment, with or without clonidine, on cognitive abilities and Alzheimer's disease-like histopathology. Considering the already established involvement of sigma-1 receptors in endogenous cell plasticity mechanisms, their activation by selective agonist compounds holds promises as possibly positive contributor to disease-modifying events in neurodegenerative diseases.