Chronic Administration of Marinobufagenin in Mice Causes Mania-Like Behavior by Altering Monoamine Turnover Unaccompanied by Motor Deficits or Oxidative Stress

Cardiotonic steroids (CTS) can modulate central nervous system function through their interaction with the Na⁺,K⁺-ATPase, affecting dopaminergic transmission. While the CTS ouabain is known to induce mania-like behavior and oxidative damage, the effects of other CTS are less clear. This study examined the effects of 14-day intracerebroventricular administration of 1.5 μl 100 μM marinobufagenin (MBG) on locomotion, gait, monoamine metabolism, and oxidative stress markers (MDA, SOD, catalase, MAO-B) in C57BL/6 mice. Chronic MBG caused increased locomotor activity and time spent in the center of the open field. Unlike ouabain, chronic MBG did not impair motor function, evaluated via gait analysis. MBG elevated striatal MAO-B activity and reduced prefrontal MDA levels, with no changes in SOD or catalase, indicating that it did not cause oxidative stress. However, it did affect dopamine and serotonin metabolism. Monoamine tissue content evaluation on day 15 showed increased dopamine turnover in the striatum and brain stem, and decreased it in the thalamus. Norepinephrine levels increased in the striatum and hippocampus. Serotonin turnover increased in the prefrontal cortex. These results indicate that chronic MBG increases locomotion and reduces anxiety-like behavior through region-specific modulation of dopaminergic and serotonergic signaling distinct from that caused by ouabain.