TY - JOUR

T1 - Intracerebroventricular injection of ouabain causes mania-like behavior in mice through D2 receptor activation

AU - Lopachev, Alexander

AU - Volnova, Anna

AU - Evdokimenko, Anna

AU - Abaimov, Denis

AU - Timoshina, Yulia

AU - Kazanskaya, Rogneda

AU - Lopacheva, Olga

AU - Deal, Alex

AU - Budygin, Evgeny

AU - Fedorova, Tatiana

AU - Gainetdinov, Raul

PY - 2019/10/30

Y1 - 2019/10/30

N2 - 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.

AB - 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.

KW - ENDOGENOUS CARDIOTONIC STEROIDS

KW - SIGNAL-REGULATED KINASE

KW - DOPAMINE RELEASE

KW - ANIMAL-MODELS

KW - RAT-BRAIN

KW - HYPERACTIVITY

KW - DISORDER

KW - NEURONS

KW - LITHIUM

KW - AKT

UR - http://www.scopus.com/inward/record.url?scp=85074295582&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/intracerebroventricular-injection-ouabain-causes-manialike-behavior-mice-through-d2-receptor-activat

U2 - 10.1038/s41598-019-52058-z

DO - 10.1038/s41598-019-52058-z

M3 - Article

C2 - 31666560

AN - SCOPUS:85074295582

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 15627

ER -