Intracerebroventricular injection of ouabain causes mania-like behavior in mice through D2 receptor activation

• Published in: Scientific reports 2019-10, Vol.9 (1), p.15627-13, Article 15627
• Main Authors: Lopachev, Alexander, Volnova, Anna, Evdokimenko, Anna, Abaimov, Denis, Timoshina, Yulia, Kazanskaya, Rogneda, Lopacheva, Olga, Deal, Alex, Budygin, Evgeny, Fedorova, Tatiana, Gainetdinov, Raul
• Format: Article
• Language: English
• Subjects: 631/45; 631/45/275; 631/45/882; Affective disorders; AKT protein; Animals; Anxiety; Behavior, Animal; Bipolar Disorder - chemically induced; Bipolar Disorder - genetics; Bipolar Disorder - metabolism; Bipolar Disorder - psychology; Central nervous system; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Deactivation; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopamine D2 receptors; Dopamine receptors; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Haloperidol; Humanities and Social Sciences; Humans; Hyperactivity; Locomotor activity; Male; Metabolites; Mice; multidisciplinary; Na+/K+-exchanging ATPase; Neostriatum; Neurotoxicity; Ouabain; Ouabain - administration & dosage; Ouabain - adverse effects; Receptor mechanisms; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Rodents; Science; Science (multidisciplinary); Sodium-Potassium-Exchanging ATPase - genetics; Sodium-Potassium-Exchanging ATPase - metabolism; Steroid hormones; Ventricle; Ventricles (cerebral)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-52058-z

Intracerebroventricular (ICV) administration of ouabain, an inhibitor of the Na, K-ATPase, is an approach used to study the physiological functions of the Na, K-ATPase and cardiotonic steroids in the central nervous system, known to cause mania-like hyperactivity in rats. We describe a mouse model of ouabain-induced mania-like behavior. ICV administration of 0.5 µl of 50 µM (25 pmol, 14.6 ng) ouabain into each lateral brain ventricle results in increased locomotor activity, stereotypical behavior, and decreased anxiety level an hour at minimum. Fast-scan cyclic voltammetry showed that administration of 50 µM ouabain causes a drastic drop in dopamine uptake rate, confirmed by elevated concentrations of dopamine metabolites detected in the striatum 1 h after administration. Ouabain administration also caused activation of Akt, deactivation of GSK3β and activation of ERK1/2 in the striatum of ouabain-treated mice. All of the abovementioned effects are attenuated by haloperidol (70 µg/kg intraperitoneally). Observed effects were not associated with neurotoxicity, since no dystrophic neuron changes in brain structures were demonstrated by histological analysis. This newly developed mouse model of ouabain-induced mania-like behavior could provide a perspective tool for studying the interactions between the Na,K-ATPase and the dopaminergic system.