Sleep deprivation is associated with increased circulating levels of endogenous ouabain: Potential role in bipolar disorder.

• 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]