The Alpha2-Adrenoceptor Antagonist Dexefaroxan Enhances Hippocampal Neurogenesis by Increasing the Survival and Differentiation of New Granule Cells

Abstract

The generation of new neurons in the hippocampus is a dynamic process regulated by environmental, endocrine, and pharmacological factors. Since enhancement of hippocampal neurogenesis has been associated with learning and memory, and the locus coeruleus-noradrenergic system has been shown to modulate these cognitive functions, we hypothesized that activation of noradrenergic neurotransmission might enhance neurogenesis in the adult hippocampus. To test this hypothesis in vivo, we induced the release of noradrenaline in the hippocampus by blocking presynaptic inhibitory autoreceptors with the selective alpha2-adrenoceptor antagonist dexefaroxan. Confocal microscopy showed that noradrenergic afferents make contact with proliferating and differentiating cells, suggesting a direct noradrenergic influence on neurogenesis. Chronic systemic treatment of rats with dexefaroxan did not affect cell proliferation per se in the dentate gyrus (as monitored by bromodeoxyuridine-labeling), but promoted the long-term survival of newborn neurons by reducing apoptosis. Dexefaroxan treatment also enhanced the number and complexity of the dendritic arborizations of polysialated neural cell adhesion molecule-positive neurons. The trophic effects of dexefaroxan on newborn cells might involve an increase in brain-derived neurotrophic factor, which was upregulated in afferent noradrenergic fiber projection areas and in neurons in the granule cell layer. By promoting the survival of new endogenously formed neurons, dexefaroxan treatment represents a potential therapeutic strategy for maintaining adult neurogenesis in neurodegenerative conditions, such as Alzheimer's disease, that affect the hippocampus.