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

Abstract

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.

Current State and Future Directions of Intranasal Delivery Route for Central Nervous System Disorders: A Scientometric and Visualization Analysis

“…Consequently, numerous studies have proposed promising strategies to improve the delivery of therapeutic agents to the brain by circumventing or overcoming the BBB during the last decades. These strategies include intracerebroventricular injections (Lopachev et al, 2019), convection enhanced delivery (Zhan and Wang, 2018), inhibition of efflux transporters (Sanchez-Covarrubias et al, 2014), chemical modification (Al-Ahmady, 2018), and the application of hyperosmotic agents (Patel et al, 2009) or focused ultrasound (Dauba et al, 2020;Lin et al, 2020;Wu et al, 2021a), and so on. However, the limitation of these administration routes is marred by safety concerns, invasive, and erratic efficacy.…”

Ouabain-Induced Gene Expression Changes in Human iPSC-Derived Neuron Culture Expressing Dopamine and cAMP-Regulated Phosphoprotein 32 and GABA Receptors

“…CTS are considered to be endogenous regulators, or hormone-like compounds [ 1 , 2 , 17 , 18 , 19 ]. It is known that CTS can significantly affect dopamine neurotransmission through affecting the function of DAT or dopamine receptors [ 20 , 21 ]. Intracerebroventricular (ICV) CTS injection causes bipolar disorder-like behavior in rodents [ 21 , 22 ], which may be accompanied by neuron damage [ 22 , 23 ].…”

“…It is known that CTS can significantly affect dopamine neurotransmission through affecting the function of DAT or dopamine receptors [ 20 , 21 ]. Intracerebroventricular (ICV) CTS injection causes bipolar disorder-like behavior in rodents [ 21 , 22 ], which may be accompanied by neuron damage [ 22 , 23 ]. In the amphetamine mania model in rats it was shown that intracerebroventricular injection of CTS antibodies neutralizes the effects of amphetamine administration [ 24 ] which means that not only exogenous but also endogenous CTS may contribute to mania-like behavior.…”

“…In the amphetamine mania model in rats it was shown that intracerebroventricular injection of CTS antibodies neutralizes the effects of amphetamine administration [ 24 ] which means that not only exogenous but also endogenous CTS may contribute to mania-like behavior. As we have previously shown, ICV injection of ouabain in mice causes mania-like behavior, decreased dopamine reuptake, and an increase in phosphorylation of ERK1/2, Akt, and GSK3β in striatal tissue [ 21 ]. Alterations in behavior and activity of signaling cascades were significantly affected by administration of D2 dopamine receptor antagonist haloperidol [ 21 ].…”

“…As we have previously shown, ICV injection of ouabain in mice causes mania-like behavior, decreased dopamine reuptake, and an increase in phosphorylation of ERK1/2, Akt, and GSK3β in striatal tissue [ 21 ]. Alterations in behavior and activity of signaling cascades were significantly affected by administration of D2 dopamine receptor antagonist haloperidol [ 21 ]. In the striatum, dopaminergic projections innervate GABAergic medium spiny neurons which express D1- and D2-like dopamine receptors and an integrator of dopamine neurotransmission dopamine and cAMP-regulated phosphoprotein 32 (DARPP-32) [ 25 , 26 , 27 ].…”