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Background: Lithium (Li) is the prototypic mood-stabilizing drug, but the individual response to Li is highly heterogeneous. Some evidence suggest interactions between Li and stress, and it is possible to hypothesize that lithium’s effects are modified by stress conditions. The current study examines the interaction between 2 chronic stressors, constant light (CL) and restrain and the behavioral responses to chronic Li in female and male mice. Methods: Female and male ICR mice were exposed to 3 weeks of either (1) CL; (2) daily restrain or (3) no stress control. One week after the start of the stress intervention, mice started chronic oral Li treatment or control. After 2 weeks of stress and Li, mice were tested in a number of behavioral tests including spontaneous activity, sweet solution preference, plus-maze and forced swim test. Results: There were no effects of stressors on behavior. Effects of Li were demonstrated in males but not females with no interactions between stress and Li. Conclusions: The behavioral effects of Li in this study were not affected by stress. The lack of effects of the stressors themselves on behavior suggests that the application of more intrusive stressors might be needed to further explore the issue.

The acute antidepressant effects of ketamine provide hope for the development of a fast acting approach to treat depression but the consequences of chronic treatment with ketamine are still unclear. One theory regarding the acute effect is that ketamine acts through activation of mTOR but chronic activation of mTOR may lead to reduced autophagy and reduced autophagy could have negative consequences on neuronal plasticity and survival and on affect. To study the interaction between chronic ketamine administration, autophagy and depression the present study tested the effects of 3 weeks daily administration of 5 or 10mg/kg ketamine in both female and male ICR mice on behavior in the open field and the forced swim test and on frontal cortex levels of beclin-1 and p62, two proteins that serve as markers of autophagy. The results show that acute administration of ketamine results in an antidepressant-like effect in the FST, chronic ketamine had no effects in the behavioral tests. There was no difference in the acute or chronic groups between female and male mice. Additionally, chronic ketamine did not alter frontal cortex levels of autophagy markers. The present study suggests that in ICR mice, chronic ketamine does not have the same clear effects that are seen after acute treatment. The lack of difference between females and males and the lack of effects on autophagy after chronic treatment is discussed.

Background AMPA receptors are highly expressed throughout the central nervous system and are suggested to be involved in mood regulation. Studies found changes in glutamate, its metabolites and receptors in patients with bipolar disorder (BPD) or major depression (MD) and in animal models of stress. Additional data suggest that the glutamatergic system and AMPA receptors specifically, have an important role in modulating the therapeutic effects of mood stabilizers. Further research on the role of AMPA receptors in mood regulation can be done using AMPAkines, positive modulators of AMPA receptors. AMPAkines have been studied for cognitive enhancement in neurodegenerative disorders and some were also examined in preclinical studies of mood disorders. In that context, the present study was designed to test the effects of the AMPAkine CX717 in a strain specific battery of tests for mania-like behaviors. Methods Black Swiss male mice were sub-chronically treated with 5 different doses of CX717 or vehicle and tested in a battery of behavioral tests including spontaneous activity, sweet solution preference, resident-intruder, forced swim and amphetamine-induced hyperactivity. Results Data show that CX717 doses of 30 mg/kg and above, but not lower, reduce activity levels. Moreover, 45 mg/kg and above reduce interactions in the resident-intruder test and ameliorate amphetamine-induced hyperactivity. Conclusions The results therefore show a partial effect of CX717 on manic-like behavior, somewhat similar to previously demonstrated effects of atypical antipsychotic drugs in this strain. It is therefore suggested that further work related to AMPAkines in the treatment of affective disorders might be warranted.

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.

The disaccharide trehalose protects cells from hypoxic and anoxic injury and suppresses protein aggregation. In vivo studies with trehalose show cellular and behavioral beneficial effects in animal models of neurodegenerative diseases. Moreover, trehalose was shown to enhance autophagy, a process that had been recently suggested to be involved in the therapeutic action of antidepressant and mood-stabilizing drugs.The present study was therefore designed to explore antidepressant and mood-stabilizing activity of trehalose in animal models for depression and mania.Trehalose 1 or 2% was administered for 3 weeks as a drinking solution to Black Swiss mice (a model of manic-like behaviors) or 2% to ICR mice and their behavior evaluated in a number of tests related to depression or mania. The effects of trehalose were compared with similar chronic administration of the disaccharide maltose as well as with a vehicle (water) control.Chronic administration of trehalose resulted in a reduction of frontal cortex p62/beclin-1 ratio suggesting enhancement of autophagy. Trehalose had no mood-stabilizing effects on manic-like behavior in Black Swiss mice but instead augmented amphetamine-induced hyperactivity, an effect similar to antidepressant drugs. In ICR mice, trehalose did not alter spontaneous activity or amphetamine-induced hyperactivity but in two separate experiments had a significant effect to reduce immobility in the forced swim test, a standard screening test for antidepressant-like effects.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.

ObjectiveA number of atypical antipsychotic drugs were demonstrated to have anxiolytic effects in patients and in animal models. These effects were mostly suggested to be the consequence of the drugs’ affinity to the serotonin system and its receptors. Asenapine is a relatively new atypical antipsychotic that is prescribed for schizophrenia and for bipolar mania. Asenapine has a broad pharmacological profile with significant effects on serotonergic receptors, hence it is reasonable to expect that asenapine may have some anxiolytic effects. The present study was therefore designed to examine possible effects of asenapine on anxiety-like behaviour of mice.MethodMale ICR mice were repeatedly treated with 0.1 or 0.3 mg/kg injections of asenapine and then tested in a battery of behavioural tests related to anxiety including the open-field test, elevated plus-maze (EPM), defensive marble burying and hyponeophagia tests. In an adjunct experiment, we tested the effects of acute diazepam in the same test battery.ResultsThe results show that diazepam reduced anxiety-like behaviour in the EPM, the defensive marble burying test and the hyponeophagia test but not in the open field. Asenapine has anxiolytic-like effects in the EPM and the defensive marble burying tests but had no effects in the open-field or the hyponeophagia tests. Asenapine had no effects on locomotor activity.ConclusionThe results suggest that asenapine may have anxiolytic-like properties and recommends that clinical trials examining such effects should be performed.

Black Swiss (BS) mice were shown to be an advantageous strain to model behavioral domains of mania, but to date only male mice were tested, whereas bipolar disorder (BPD) is equally prevalent in women and men. This study was therefore designed to examine the possibility of using both male and female BS mice in future studies. Groups of male and female BS mice were compared with each other, with or without lithium treatment, in tests for domains of mania-like behavior including activity in an open field, sweet solution preference, elevated plus maze, forced swim and amphetamine-induced hyperactivity. The results indicate mostly a similarity between female and male BS mice, both naïve and after chronic lithium treatment. The results are discussed in the context of the deficiency in utilizing female mice in animal models research and suggest that both male and female BS mice can be used to model domains of mania-like behavior.

ObjectiveThe underlying biology of bipolar disorder and the mechanisms by which effective medications induce their therapeutic effects are not clear. Appropriate use of animal models are essential to further understand biological mechanisms of disease and treatment, and further understanding the therapeutic mechanism of mood stabilisers requires that clinically relevant administration will be effective in animal models. The clinical regimens for mood-stabilising drugs include chronic oral administration; however, much of the work with animal models includes acute administration via injection. An effective chronic and oral administration of the prototypic mood stabiliser lithium was already established and the present study was designed to do the same for the mood stabiliser carbamazepine.MethodsMice were treated for 3 weeks with carbamazepine in food. ICR mice were treated with 0.25%, 0.5% and 0.75%, and C57bl/6 mice with 0.5% and 0.75%, carbamazepine in food (w/w, namely, 2.5, 5.0 or 7.5 g/kg food). Mice were then tested for spontaneous activity, forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperactivity.ResultsOral carbamazepine administration resulted in dose-dependent blood levels reaching 3.65 μg/ml at the highest dose. In ICR mice, carbamazepine at the 0.5% dose had no effect on spontaneous activity, but significantly reduced immobility in the TST by 27% and amphetamine-induced hyperactivity by 28%. In C57bl/6 mice, carbamazepine at the 0.75% dose reduced immobility time in the FST by 26%.ConclusionsThese results demonstrate a behaviourally effective oral and chronic regimen for carbamazepine with mood stabilising-like activity in a standard model for mania-like behaviour and two standard models for depression-like behaviour.

Animal models are crucial components in the search for better understanding of the biological basis of psychiatric disorders and for the development of novel drugs. Research, in general, and research with animal models, in particular, relies on the consistency of effects of investigated drugs or manipulations across experiments. In that context, it had been noted that behavioral responses to lithium in ICR (CD-1) mice from Harlan Israel have changed across the last years. To examine this change, the present study compared the effect of lithium treatment in ICR mice from Harlan Israel with the ICR mice from Harlan USA. The mice were treated with chronic oral lithium. Their lithium serum levels were measured and their behavior in the forced swim test (FST) was evaluated. The mice were also treated with [(3)H]-inositol ICV and lithium injection and their frontal cortex [(3)H]-phosphoinositols accumulation was measured. Results show that lithium serum levels in Israeli mice were significantly lower compared with the USA mice, that lithium had no behavioral effect in the Israeli mice but significantly reduced FST immobility time of the USA mice, and that phosphoinositols accumulation was much more strongly affected by lithium in the USA mice compared with the Israeli mice. These results suggest that the Israeli Harlan colony of ICR mice changed significantly from the original ICR colony in Harlan USA and that the differences might be related to absorption or secretion of lithium.