Paradoxical changes in mood-related behaviors on continuous social isolation after weaning.

Continuous social isolation (SI) from an early developmental stage may have different effects in youth and adulthood. Moreover, SI is reported to impair neuronal plasticity. In this study, we used post-weaning rats to compare the impact of continuous SI on depressive-like, anxiety-related, and fear-related behaviors and neuronal plasticity in puberty and adulthood. Furthermore, we assessed the effect of lithium on behavioral changes and neuronal plasticity. Continuous SI after weaning induced depressive-like behaviors in puberty; however, in adulthood, depressive-like and anxiety-related behaviors did not increase, but-paradoxically-decreased in comparison with the controls. The decreased expression of neuronal plasticity-related proteins in the hippocampus in puberty was more prominent in the prefrontal cortex and hippocampus in adulthood. In contrast, SI after weaning tended to decrease fear-related behaviors in puberty, a decrease which was more prominent in adulthood with increased neuronal plasticity-related protein expression in the amygdala. Lithium administration over the last 14 days of the SI-induced period removed the behavioral and expression changes of neuronal plasticity-related proteins observed in puberty and adulthood. Our findings suggest that the extension of the duration of SI from an early developmental stage does not simply worsen depressive-like behaviors; rather, it induces a behavior linked to neuronal plasticity damage. Lithium may improve behavioral changes in puberty and adulthood by reversing damage to neuronal plasticity. The mechanisms underlying the depressive-like and anxiety-related behaviors may differ from those underlying fear-related behaviors.

Effects of antidepressants and mood stabilizers on serum levels of adiponectin.

The effect of antidepressants and mood stabilizers on serum levels of adiponectin was investigated. Fluvoxamine (30 and 50 mg/kg/day) or lithium (40 and 60 mg/kg/day) was dissolved in distilled water and administered orally to rats every day for 4 weeks. Fluvoxamine (50 mg/kg/day) alone significantly elevated the serum level of adiponectin, but no significant difference was found between other drug-treated groups and the control group. This difference of these drugs' effectiveness on serum adiponectin might contribute to their differences of action mechanisms and therapeutic effects.

The co-occurrence of zinc deficiency and social isolation has the opposite effects on mood compared with either condition alone due to changes in the central norepinephrine system.

Nutritional and social environmental problems during the early stages of life are closely associated with the pathophysiology of mood disorders such as depression. Disruption or dysfunction of the central norepinephrine (NE) system is also considered to play a role in mood disorders. Therefore, we evaluated the effects of zinc deficiency and/or social isolation on mood and changes in the central NE system using rats. Compared with the controls, the rats subjected to zinc deficiency or social isolation alone exhibited increased anxiety-related behavior in the elevated plus maze and greater depression-like behavior in the forced swim test. However, the co-occurrence of zinc deficiency and social isolation resulted in decreased anxiety-related behavior and control levels of depression-like behavior. Social isolation alone decreased the rats' cerebral NE concentrations. The expression of the NE transporter was not affected by social isolation alone, but its expression in the locus coeruleus was markedly decreased by the co-occurrence of social isolation and zinc deficiency, and this change was accompanied by an increase in the blood concentration of 3-methoxy-4-hydroxyphenylglycol, which is a marker of central NE system activity. These findings suggest that zinc deficiency or social isolation alone induce anxious or depressive symptoms, but the presence of both conditions has anxiolytic or antidepressive effects. Furthermore, these opposing effects of mood-related behaviors were found to be associated with changes in the central NE system.

Mania: not the opposite of depression, but an extension? Neuronal plasticity and polarity.

What underlies bipolar disorder? What pathophysiologic process can produce symptoms that are apparently polar opposites? Recent studies of neuronal plasticity suggest a mechanism. Both zinc deficiency and social isolation impair neuronal plasticity; both are associated with major depression. Yet when zinc deficiency and social isolation occur together, they are associated with aggression, not with depression. On that basis, and according to additional findings in rats reported herein, it was inferred that moderate impairment of neuronal plasticity induces a depressive state, but that further impairment of neuronal plasticity induces not more depression, but a manic state. However, not only neuronal plasticity, but also some kind of load toward neuronal function can influence polarity or symptoms of mood disorder. Our hypothesis is that mania is an extension of depression from the perspective of neuronal plasticity, and that multiaxial evaluation by neuronal plasticity and neuronal load is useful to elucidate the pathophysiology of mood disorder. Using this hypothesis, many clinical aspects that have been heretofore difficult to interpret can be understood. A mood stabilizer or electric convulsive therapy is often used for the treatment of mood disorder, but it has remained unclear why such therapies are useful for both mania and depression. This hypothesis can explain how mood stabilizers or electric convulsive therapy can improve both mania and depression through the recovery of neuronal plasticity. It is difficult to explain the pathophysiology of manic switching by antidepressants solely from the perspective of the impairment of neuronal plasticity. To interpret this phenomenon, the action of antidepressants to neuronal load should be regarded as the other axis from neuronal plasticity. Based on this hypothesis, it is expected that the pathophysiology of mood disorder and clinical mechanism of mood stabilizers and antidepressants can be understood in an integrated manner.

Effect of dietary zinc deficiency on ischemic vulnerability of the brain.

Deficiency of zinc, which modulates glutamate release, might increase ischemic vulnerability of the brain. We examined effects of dietary zinc deficiency for 2 weeks on ischemic vulnerability in several brain regions using dynamic positron autoradiography technique and [18F]2-fluoro-2-deoxy-d-glucose with rat brain slices. In the normal diet group, the cerebral glucose metabolic rate (CMRglc) was not significantly different from that of the ischemia-unloaded control even after the loading of ischemia for 45 min. However, in the zinc-deficient diet group, CMRglc was significantly lower than that of the ischemia-unloaded control after loading of ischemia for 45 min. With treatment of MK-801 (NMDA receptor antagonist) from the start of ischemia loading, CMRglc was not significantly different from that of the ischemia-unloaded control. These findings, obtained for all analyzed brain regions, suggest that dietary zinc deficiency increased ischemic vulnerability in the brain, and that glutamate might contribute to this effect through activation of the NMDA receptor.