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Background: Endogenous ouabain (EO) and atrial natriuretic peptide (ANP) are important in regulation of sodium and fluid balance. There is indirect evidence that ANP may be involved in the regulation of endogenous cardenolides., Methods: H295R are human adrenocortical cells known to release EO. Cells were treated with ANP at physiologic concentrations or vehicle (0.1% DMSO), with or without guanylyl cyclase inhibitor 1,2,4 oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Cyclic guanosine monophosphate (cGMP), the intracellular second messenger of ANP, was measured by a chemiluminescent immunoassay and EO was measured by radioimmunoassay of C18 extracted samples., Results: EO secretion is inhibited by ANP treatment, with the most prolonged inhibition (90 min vs ≤ 60 min) occurring at physiologic ANP concentrations (50 pg/mL). Inhibition of guanylyl cyclase with ODQ, also reduces EO secretion. The inhibitory effects on EO release in response to cotreatment with ANP and ODQ appeared to be additive., Conclusions: ANP inhibits basal EO secretion, and it is unlikely that this is mediated through ANP-A or ANP-B receptors (the most common natriuretic peptide receptors) or their cGMP second messenger; the underlying mechanisms involved are not revealed in the current studies. The role of ANP in the control of EO synthesis and secretion in vivo requires further investigation., Competing Interests: I have read the journal’s policy and Dr. El-Mallakh is on the speakers’ bureaus of Eisai, Indivior, Intra-Cellular Therapies, Janssen, Lundbeck, Noven, Otsuka, Sunovion, and Teva. The other authors of this manuscript do not have any competing interest.

In the only bipolar cycling in vitro model, rat hippocampal slices are treated with the sodium pump inhibitor ouabain, which induces epileptiform activity, followed by refractory activity loss that recovers and cycles back to epileptiform activity. Thus, clinical cycling seen in patients with bipolar disorder is modeled on a cellular level as alternating hyperactivity and hypoactivity interspersed with normal activity. In this study, we tested the ability of cariprazine a new antipsychotic candidate to block ouabain-induced changes in rat hippocampal slices. Cycling of population spikes and epileptiform bursts was evoked using an extracellular stimulation electrode located in the Schaeffer collaterals of 400-µm-thick rat hippocampal slices treated with ouabain (3.3μM) alone or in combination with cariprazine (1, 5, 25, and 50µM). Responses were recorded using an extracellular electrode placed in the cell body layer of the CA1 region. Cariprazine 25 and 50µM delayed ouabain-induced epileptiform burst onset and subsequent activity loss. Lower cariprazine concentrations were ineffective. Cariprazine delays the onset of ouabain-induced epileptiform bursts and the loss of spiking activity similarly to that previously demonstrated with the mood stabilizer lithium. These results suggest that cariprazine may have therapeutic potential for treatment of bipolar disorder., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

While the pathophysiologic mechanisms of bipolar illness are unknown, a dysregulation of electrolytes, particularly intracellular sodium (Na) and calcium (Ca), are thought to contribute to the illness. Ouabain, a potent Na pump inhibitor, administered intracerebroventricularly (ICV), has been used previously to model mania. The current study evaluates the effect of ICV ouabain on Na pump isoform expression in rat brain. Animals received 5 microl ICV of either 10(-3) M ouabain or artificial cerebrospinal fluid (aCSF). They were then sacrificed 7 days after the ICV injection and specific brain areas were dissected and frozen until the assay (frontal cortex, hippocampus, and basal ganglia). The three isoforms of the alpha subunit of the Na pump that are expressed in the brain were quantified with immunoblot analysis with actin serving as internal control. The behavioral hyperactivity seen in rats receiving ICV ouabain is associated with an increase of expression of the glial-specific alpha2 isoform in the basal ganglia, and the neuron-specific alpha3 isoforms in the frontal cortex. These findings, in association with human post mortem studies finding that alpha2 is underexpressed in the temporal cortex of bipolar subjects, suggest that Na pump isoform expression may be of interest in the pathophysiology of mania.

Endogenous cardenolides are digoxin-like substances and ouabain-like substances that have been implicated in the pathogenesis of hypertension and mood disorders in clinical and pre-clinical studies. Regulatory signals for endogenous cardenolides are still unknown. These endogenous compounds are believed to be produced by the adrenal gland in the periphery and the hypothalamus in the central nervous system, and constitute part of an hormonal axis that may regulate the catalytic activity of the α subunit of Na(+)/K(+)-ATPase. A review of literature suggests that there is great overlap in physiological environments that are associated with either elevations or reductions in the levels of atrial natriuretic peptide (ANP) and endogenous cardenolides. This suggests that these two factors may share a common regulatory signal or perhaps that ANP may be involved in the regulation of endogenous cardenolides. [ABSTRACT FROM AUTHOR]

Abstract: Memantine, a selective antagonist of the N-methyl-D-aspartate receptor, is approved for the treatment of moderate to severe Alzheimer''s disease. Ion dysregulation is thought to be involved in the pathophysiology of bipolar illness, suggesting that memantine may be effective in treating bipolar manic and/or depressive episodes. We utilized two preclinical models of mania that mimic pathophysiologic changes seen in bipolar illness to examine the potential efficacy of memantine in the treatment of this disorder. Locomotor hyperactivity of male Sprague–Dawley rats in an open field was induced with intracerebroventricular (ICV) administration of 10−3 M ouabain. Memantine (2.5, 5 or 7.5mg/kg), lithium (6.75mEq/kg), or vehicle were administered acutely via intraperitoneal injection immediately prior to ouabain, then chronically for 7days (oral memantine 20, 30, and 40mg/kg/day in water; lithium 2.4g/kg food). In a second model of bipolar disorder, cycling between population spikes and epileptiform bursts was investigated in rat hippocampal slices treated with ouabain (3.3μM) alone or in combination with memantine (0.5, 1.0, and 5.0μM). Ouabain-induced hyperlocomotion was normalized with acute and chronic lithium and chronic use of memantine. Memantine delayed the onset of ouabain-induced-cycling in hippocampal slices. Memantine may have antimanic properties. [Copyright &y& Elsevier]

• Sleep fragmentation results in elevation of the endogenous sodium pump regulator, endogenous ouabain. • Sodium pump alpha2 knockout mice, which express half as much of the sodium pump protein as wild type mice, have elevated endogenous ouabain at baseline, and sleep fragmentation does not result in additional elevations. • Sodium pump alpha2 knockout mice express manic-like behavior at baseline. • These results provide potential mechanism between stressors (such as sleep disturbance) and manic symptoms in the sodium pump hypothesis for bipolar disorder. Endogenously produced cardiac glycosides, like endogenous ouabain (EO), are putative hormones that have been implicated in the pathophysiology of bipolar disorder. Individuals with bipolar disorder appear to be unable to sufficiently upregulate production of EO in situations of increased need. This study was performed to determine the effect of sleep deprivation on the circulating levels of EO. Plasma EO concentrations were measured by ouabain-radioimmunoassay in heterozygote Na,K-ATPase a2 knockout (KO) mice, which have been used as an animal model of mania, and wildtype siblings at baseline and after sleep fragmentation utilizing the moving bar method. a2 KO animals had elevated endogenous ouabain concentrations compared to wild type controls (0.82 ± SD 0.22 nM vs 0.26 ± 0.02, P = 0.03). Sleep fragmentation increased ouabain concentrations in wild type mice (0.53 ± 0.08 nM sleep fragmentation vs 0.26 ± 0.02 nM baseline, P = 0.04), but not in a2 KO mice (0.60 ± 0.07 nM sleep fragmentation vs 0.82 ± 0.22 nM baseline, P > 0.05). These studies demonstrate that sleep disturbance can increase EO in control mice but animals that exhibit some manic behaviors are unable to increase EO production. [ABSTRACT FROM AUTHOR]

Abstract: Intracerebroventricular (ICV) administration of ouabain to young adult rats has been suggested to model human bipolar mania. In the human condition, mania and bipolar depression are both associated with reductions in frontal cerebral metabolism. We utilized [18F]-fluorodeoxyglucose [18FDG] positron emission tomography (PET) to visualize glucose uptake in animals receiving ICV ouabain. Animals received 5 µl of 10− 3 M ouabain ICV, were anesthetized with isoflurane inhalation, and administered intraperitoneally with 0.5 mCi of 18FDG. PET data were collected over 20 min 1 hour later. Additionally, the effect of lithium was examined in animals receiving lithium in their diet for 1 week before the ICV ouabain injection. Data were analyzed with IDL Virtual Machine software. Brain glucose utilization as measured by 18FDG uptake was significantly reduced in animals receiving ICV ouabain compared with those receiving equal volumes of artificial cerebrospinal fluid. Pretreatment with lithium normalized 18FDG uptake. These results mirror human studies. [Copyright &y& Elsevier]