Na+, K+-ATPase inhibition causes hyperactivity and impulsivity in mice via dopamine D2 receptor-mediated mechanism

Kurauchi, Yuki; Yoshimaru, Yuko; Kajiwara, Yuto; Yamada, Taishi; Matsuda, Kosei; Hisatsune, Akinori; Seki, Takahiro; Katsuki, Hiroshi

doi:10.1016/j.neures.2018.10.001

Cited by 13 publications

(5 citation statements)

References 49 publications

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“…Furthermore, hyperactive dopamine transporter knockout (DAT-KO) mice with an increased amount of extracellular dopamine are considered to be a model for psychiatric disorders associated with enhanced dopaminergic transmission 33–35 , which further suggests that ouabain causes hyperactivity by decreasing dopamine reuptake in the striatum. Recently it has been shown that mice become hyperactive 7 days after ICV administration of 0.625 nmol of ouabain 36 , however, to date, there has been no model of mania-like behavior in mice similar to the aforementioned rat model, where animals become hyperactive immediately after ouabain injection. Such a model could provide evidence of Na,K-ATPase interaction with the dopaminergic system on an object different from the rat model, as well as a more rapid and less expensive tool for studying the interaction between the Na,K-ATPase and the dopaminergic system.…”

Section: Introductionmentioning

confidence: 99%

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

Лопачев

Volnova

Evdokimenko

et al. 2019

Sci Rep

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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.

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Section: Introductionmentioning

confidence: 99%

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

Лопачев

Volnova

Evdokimenko

et al. 2019

Sci Rep

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“…After 8 days, the animals developed signs of mania-like behavior accompanied by c-fos activation. Administration of lithium chloride and haloperidol also neutralized the effects of ouabain in this model [50].…”

Section: Using Cardiotonic Steroids To Model Dopaminergic System Dysf...mentioning

confidence: 63%

Na+,K+-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies

Markina,

Kazanskaya,

Timoshina

et al. 2023

Biomedicines

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In recent years, enough evidence has accumulated to assert that cardiotonic steroids, Na+,K+-ATPase ligands, play an integral role in the physiological and pathophysiological processes in the body. However, little is known about the function of these compounds in the central nervous system. Endogenous cardiotonic steroids are involved in the pathogenesis of affective disorders, including depression and bipolar disorder, which are linked to dopaminergic system dysfunction. Animal models have shown that the cardiotonic steroid ouabain induces mania-like behavior through dopamine-dependent intracellular signaling pathways. In addition, mutations in the alpha subunit of Na+,K+-ATPase lead to the development of neurological pathologies. Evidence from animal models confirms the neurological consequences of mutations in the Na+,K+-ATPase alpha subunit. This review is dedicated to discussing the role of cardiotonic steroids and Na+,K+-ATPase in dopaminergic system pathologies—both the evidence supporting their involvement and potential pathways along which they may exert their effects are evaluated. Since there is an association between affective disorders accompanied by functional alterations in the dopaminergic system and neurological disorders such as Parkinson’s disease, we extend our discussion to the role of Na+,K+-ATPase and cardiotonic steroids in neurodegenerative diseases as well.

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“…Intragastrically-injected digoxin at high doses downregulated locomotor activity by systemic effect 16 . Conversely, intracerebroventricular injection of high-dose ouabain into brain inducing Na/K ATPase inhibition caused hyperactivity in mice 25 . On the other hand, the effect of 650 µg/kg digoxin on locomotor activity seems to coincide with that on rotarod test; the negative effects on locomotor activity and rotarod performance on Days 1-3 in NT-WT mice was more severe than that in NT-KO mice, which implied that a decrease in locomotor activity could cause a reduction in rotarod performance.…”

Section: Discussionmentioning

confidence: 95%

Effects of cardiac glycoside digoxin on dendritic spines and motor learning performance in mice

Hashimoto¹,

Fujita²,

Tanimoto³

et al. 2023

Preprint

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Synapse formation following the generation of postsynaptic dendritic spines is essential for motor learning and functional recovery after brain injury. The C -terminal fragment of agrin cleaved by neurotrypsin induces dendritic spine formation in the adult hippocampus. Since the α3 subunit of sodium-potassium ATPase (Na/K ATPase) is a neuronal receptor for agrin in the central nervous system, cardiac glycosides might facilitate dendritic spine formation and subsequent improvements in learning. This study investigated the effects of the cardiac glycoside digoxin on dendritic spine turnover and learning performance in mice. Golgi-Cox staining revealed that intraperitoneal injection of digoxin less than its IC50 in brain significantly increased the density of long spines (≥2 µm) in cerebral cortex and hippocampus in wild-type mice and neurotrypsin-knockout (NT-KO) mice showing impairment of activity-dependent spine formation. Whereas motor learning performance of NT-KO mice showed significantly lower than control wild-type mice under the control condition, low dose of digoxin enhanced performance to a similar degree in both strains. In NT-KO mice, lower doses of digoxin equivalent to clinical doses also significantly improved performance. These data suggest that lower doses of digoxin could modify dendritic spine formation or recycling and facilitate motor learning in compensation for the neurotrypsin-agrin pathway.

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Na+, K+-ATPase inhibition causes hyperactivity and impulsivity in mice via dopamine D2 receptor-mediated mechanism

Cited by 13 publications

References 49 publications

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

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

Na+,K+-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies

Effects of cardiac glycoside digoxin on dendritic spines and motor learning performance in mice

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