The results suggest that trehalose may have antidepressant-like properties. It is hypothesized that these behavioral changes could be related to trehalose effects to enhance autophagy.
Lithium is the prototype mood stabilizer but its mechanism is still unresolved. Two hypotheses dominate—the consequences of lithium's inhibition of inositol monophosphatase at therapeutically relevant concentrations (the ‘inositol depletion' hypothesis), and of glycogen-synthase kinase-3. To further elaborate the inositol depletion hypothesis that did not decisively determine whether inositol depletion per se, or phosphoinositols accumulation induces the beneficial effects, we utilized knockout mice of either of two inositol metabolism-related genes—IMPA1 or SMIT1, both mimic several lithium's behavioral and biochemical effects. We assessed in vivo, under non-agonist-stimulated conditions, 3H-inositol incorporation into brain phosphoinositols and phosphoinositides in wild-type, lithium-treated, IMPA1 and SMIT1 knockout mice. Lithium treatment increased frontal cortex and hippocampal phosphoinositols labeling by several fold, but decreased phosphoinositides labeling in the frontal cortex of the wild-type mice of the IMPA1 colony strain by ~50%. Inositol metabolites were differently affected by IMPA1 and SMIT1 knockout. Inositoltrisphosphate administered intracerebroventricularly affected bipolar-related behaviors and autophagy markers in a lithium-like manner. Namely, IP3 but not IP1 reduced the immobility time of wild-type mice in the forced swim test model of antidepressant action by 30%, an effect that was reversed by an antagonist of all three IP3 receptors; amphetamine-induced hyperlocomotion of wild-type mice (distance traveled) was 35% reduced by IP3 administration; IP3 administration increased hippocampal messenger RNA levels of Beclin-1 (required for autophagy execution) and hippocampal and frontal cortex protein levels ratio of Beclin-1/p62 by about threefold (p62 is degraded by autophagy). To conclude, lithium affects the phosphatidylinositol signaling system in two ways: depleting inositol, consequently decreasing phosphoinositides; elevating inositol monophosphate levels followed by phosphoinositols accumulation. Each or both may mediate lithium-induced behavior.
We mimicked mild mitochondrial-distress robustly reported in bipolar-disorder (BD) by chronic exposure to uniquely low doses of inhibitors of mitochondrial-respiration complexes in vitro and in vivo. Exposure of the neuronal-originating SH-SY5Y cells to very low dose (10 pM) rotenone, a mitochondrial-respiration complex (Co)I inhibitor, for 72 or 96 h did not affect cell viability and reactive oxygen species (ROS) levels. Yet, it induced a dual effect on mitochondrial-respiration: overshooting statistically significant several-fold increase of most oxygen-consumption-rate (OCR) parameters vs. significantly decreased all OCR parameters, respectively. Chronic low doses of 3-nitropropionic acid (3-NP) (CoII inhibitor) did not induce long-lasting changes in the cells’ mitochondria-related parameters. Intraperitoneal administration of 0.75 mg/kg/day rotenone to male mice for 4 or 8 weeks did not affect spontaneous and motor activity, caused behaviors associated with mania and depression following 4 and 8 weeks, respectively, accompanied by relevant changes in mitochondrial basal OCR and in levels of mitochondrial-respiration proteins. Our model is among the very few BD-like animal models exhibiting construct (mild mitochondrial dysfunction), face (decreased/increased immobility time in the forced-swim test, increased/decreased consumption of sweet solution, increased/decreased time spent in the open arms of the elevated plus maze) and predictive (reversal of rotenone-induced behavioral changes by lithium treatment) validity. Our rotenone regime, employing doses that, to the best of our knowledge, have never been used before, differs from those inducing Parkinson’s-like models by not affecting ROS-levels and cell-viability in vitro nor motor activity in vivo.
Accumulated data support a relationship between mood disorders and cellular plasticity and resilience, some suggesting relevance to autophagy. Our previous data show that pharmacological enhancement of autophagy results in antidepressant-like effects in mice. The current study was designed to further examine the effects of autophagy enhancement on mood by testing the effects of subchronic treatment with the mammalian target of rapamycin (mTOR) inhibitors and autophagy enhancers rapamycin and temsirolimus in a model for mania and in a model for antidepressant action, respectively. The results show that rapamycin reduced mania-like aggression and reward-seeking behaviors, with no effects on locomotion. Temsirolimus reduced depression-related immobility in the forced-swim test without effects on locomotion in the open field or on anxiety-related measures in the elevated plus maze. Taken together with our previous findings, these data support the notion that enhancing autophagy may have mood-stabilizing effects.
The scarcity of good animal models for bipolar disorder (BPD) and especially for mania is repeatedly mentioned as one of the rate-limiting factors in the process of gaining a better understanding into its pathophysiology and of developing better treatments. Standard models of BPD have some value but usually represent only one facet of the disease and have partial validity. A number of new approaches for modeling BPD and specifically mania have been suggested in the last few years and can be combined to improve models. These approaches include targeted mutation models representing reverse translation, the identification of advantageous strains for components of the disorder, a search for the most homologous species to address specific human pathology, and the exploration of individual differences of response including the separation between susceptible and resilient animals. Additionally, recent efforts have identified and developed new tests to distinguish between "normal" and "BPD-like" animals including the different utilization of known tests and novel tests such as the female-urine-sniffing test and behavior pattern monitor analysis. Additional tests relating to further domains of BPD are still needed. An ideal model for BPD that will encompass the entire disease and be useful for every demand will probably not become available until we have a full understanding of the pathophysiology of the disorder. However, the current advances in modeling should lead to better comprehension of the disorder and therefore to the gradual development of increasingly improved models.
Asenapine is indicated for the treatment of schizophrenia and manic episodes in bipolar disorder (BPD). There is a paucity of information on the effects of asenapine in animal models of BPD, but such work is essential to discover its scope of effects and its mechanisms of therapeutic action. This study evaluated the effects of asenapine in a validated test battery for manic-like behaviors in Black Swiss mice. Male Black Swiss mice received asenapine at 0.03, 0.1, and 0.3 mg/kg twice daily for 7 days and were tested for spontaneous activity, sweet solution preference, forced-swim test, social interaction, and amphetamine-induced hyperactivity. Asenapine treatment resulted in dose-dependent, clinically relevant plasma levels. Asenapine, at the 0.1 and 0.3 mg/kg doses, reduced activity, with the 0.3 mg/kg dose also resulting in increased time in the center of an open field, increased immobility in the forced-swim test, and reduced amphetamine-induced hyperactivity. Asenapine exerted no effects in the social interaction or sweet solution preference tests. The results suggest that asenapine exerts antimanic-like effects in some of the behavioral tests performed in Black Swiss mice. These data support the utilization of asenapine in the treatment of BPD.
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