Establishment of a Battery of Simple Models for Facets of Bipolar Disorder: A Practical Approach to Achieve Increased Validity, Better Screening and Possible Insights into Endophenotypes of Disease

Abstract

The lack of appropriate animal models for bipolar disorder (BPD) hinders the translation of novel molecular and genetic findings into the development of new more efficient treatments. Attempts to develop a comprehensive model for BPD did not result in a practical and valid model and at present most studies utilize a limited number of models for specific components of the disorder. Whereas there is a higher availability of models for the depression pole of BPD, only a few models represent the manic pole with the most frequently used being psychostimulant-induced hyperactivity. This last model had been important in studies of the disease and has some validity but it is clear that by itself cannot be considered to represent mania. Additional models for facets of BPD are needed to allow better screening of new drugs and new mutant mice. Such models may also support the exploration of endophenotypes of BPD and the mechanisms of the disease. An advantage of a battery approach is that each model can be only partially valid when used alone but the combination of a few models may result in strong validity. The present study suggests that such a battery can be based on existing models previously developed in the context of studying normal behavior or other disorders after an initial validation in the context of BPD. An example for this idea is described using the resident-intruder test for aggression. Present results show that 3 weeks oral treatment with 1.2-2.4% lithium (increasing doses), or 20 g/kg daily dose of valproate, significantly reduced aggressive behavior in resident mice without affecting non-aggressive social interactions. Accordingly, it is suggested that the simplified resident-intruder paradigm may model the aggression related to mania as part of a test battery for facets of BPD. It is further speculated that, pending further research, this paradigm can be combined with additional methods to explore changes in the LHPA axis that may be linked to an important endophenotype of BPD.

Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers

“…We tested whether lithium could ameliorate the circadian phenotype observed in the Δe24 -/-mice. Mice were fed lithium-containing chow using a protocol that has been shown to result in serum lithium levels comparable to those in the therapeutic range for humans (37,38). We found that lithium rendered the circadian rhythms of the Δe24 -/-mice and that both VPA and lithium reduced the hyperactivity in the Δe24 -/-mutants.…”

Sex differences in animal models of psychiatric disorders

“…Several models have been proposed, but most of them have limited validation (Machado-Vieira et al, 2004a;Einat, 2007). In the rat sleep deprivation model of mania, at the end of the sleep deprivation period, rats present insomnia, hyperactivity and irritability.…”

Animal models of bipolar disorder and mood stabilizer efficacy: A critical need for improvement

“…Thus, the models in question generally have face validity toward the psychiatric symptoms observed in bipolar disorder. Symptoms of mania that can be modeled in animals include increased activity, irritability, reduced need for sleep (or other changes in sleep patterns), aggressive behavior, sexual drive, distractibility, and risk-taking behavior, all of which are commonly observed in human mania (Einat, 2006a). Models of the depressive phase of bipolar disorder commonly make use of models previously validated in the context of depression research.…”

“…However, there is no greater need than for bipolar disorder (Nestler et al, 2002;Einat, 2006b;Einat, 2006a;Cryan and Slattery, 2007). The limited number of suitable models for in-depth behavioral, biochemical, histological, and pharmacological analysis, has greatly hindered progress in understanding the relevant neurobiology of, and in developing novel medications for, bipolar disorder.…”