Long-term Intracerebroventricular Administration of Ouabain Causes Motor Impairments in C57Bl/6 Mice

Abstract

Introduction. Cardiac glycosides are natural ligands of Na+/K+-ATPase, which regulate its activity and signaling. Intracerebroventricular administration of ouabain has been previously shown to induce hyperlocomotion in C57Bl/6 mice via a decrease in the rate of dopamine reuptake from the synaptic cleft. Materials and methods. This study involved forty C57BL/6 mice. 1.5 μL of 50 μM ouabain was administered daily into the left lateral cerebral ventricle over the course of 4 days. On day 5, open field, beam balance, and ladder rung walking tests were performed to assess the locomotor activity and motor impairments in the mice. We evaluated changes in the activation of signaling cascades, ratios of proapoptotic and antiapoptotic proteins, and the amount of α1 and α3 isoforms of the Na+/K+-ATPase α-subunit in brain tissue using Western blotting. Na+/K+-ATPase activity was evaluated in the crude synaptosomal fractions of the brain tissues. Results. We observed hyperlocomotion and stereotypic behavior during the open field test 24 hours after the last injection of ouabain. On day 5, the completion time and the number of errors made in the beam balance and ladder rung walking tests increased in the mice that received ouabain. Akt kinase activity decreased in the striatum, whereas the ratio of proapoptotic and antiapoptotic proteins and the number of Na+/K+-ATPase α-subunits did not change. Na+/K+-ATPase activity increased in the striatum and decreased in the brainstem. Conclusions. Long-term exposure to ouabain causes motor impairments mediated by changes in the activation of signaling cascades in dopaminergic neurons.

Keywords

• na+/k+-atpase
• ouabain
• cardiac glycosides
• dopaminergic system