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Background There is a desperate need for in-vivo behavioral screening tests for anti-manic effects. The frequently used psychostimulant-induced hyperactivity test appears to have lower validity than previously described, but other quick, simple and high throughput tests are currently unavailable. New method In the context of modeling the behavioral facets of mania, we previously suggested that the sweet solution preference test (SSP) in naive mice might have predictive validity for screening anti-manic effects. The current study further examined this proposal by testing the effects of lithium, valproate and imipramine on SSP in three strains of mice (male mice from the black Swiss, ICR and C57bl/6 strains) and an exploratory test in females (black Swiss strain). Results Data demonstrate that lithium and valproate at appropriate dosing schedules significantly and reliably reduce SSP in all three strains (including in females) but that the antidepressant imipramine has no effects. Comparison with existing methods The results support the utilization of the SSP as mice screening model for anti-manic effects of drugs with stronger predictive validity compared with other methods. Conclusions The SSP is not a comprehensive model for bipolar disorder but it has good predictive validity and strong practical value that can be applied towards simple and fast screening of large numbers of animals, without the need for specialized equipment or complicated/prolonged procedures. We therefore propose that the SSP is an advantageous screening assay for testing novel mood stabilizing drugs for anti-manic properties.

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 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.

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.

Background: Lithium has numerous biochemical effects but it is difficult to dissect which of these is responsible for its therapeutic action in bipolar disorder. In the current study we aimed to address one of the major hypotheses, the inositol depletion hypothesis. This hypothesis postulates that lithium's mood-stabilizing effect is mediated by the depletion of brain inositol levels and the subsequent effect on cellular signaling. Methods: We studied whether acute intracerebroventricular (ICV) administration of myo-inositol could reverse the antidepressant-like effect of chronic lithium treatment in the forced swim test (FST). Results: In contrast with our prediction, acute myo-inositol administration did not reverse the effect of chronic lithium to decrease immobility in the FST. Conclusions: The results of the present study are limited due to the following: (1) inositol was given acutely while possible events downstream of inositol depletion might require a longer period and (2) ICV inositol may not have reached those areas of the brain involved in the FST.