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Lack of good animal models for affective disorders, including major depression and bipolar disorder, is noted as a major bottleneck in attempts to study these disorders and develop better treatments. We suggest that an important approach that can help in the development and use of better models is attention to variability between model animals.
Differences between mice strains were studied for some decades now, and sex differences get more attention than in the past. It is suggested that one factor that is mostly neglected, individual variability within groups, should get much more attention. The importance of individual differences in behavioral biology and ecology was repeatedly mentioned but its application to models of affective illness or to the study of drug response was not heavily studied. The standard approach is to overcome variability by standardization and by increasing the number of animals per group.
Possibly, the individuality of specific animals and their unique responses to a variety of stimuli and drugs, can be helpful in deciphering the underlying biology of affective behaviors as well as offer better prediction of drug responses in patients.
A 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.
Male 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.
The 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.
The results suggest that asenapine may have anxiolytic-like properties and recommends that clinical trials examining such effects should be performed.
The 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.
Mice 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.
Oral 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%.
These 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.
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