Abstract
The lack of efficient animal models for bipolar disorder (BPD), especially for the manic pole, is a major factor hindering the research of its pathophysiology and the development of improved drug treatments. The present study was designed to identify an appropriate mouse strain for modeling some behavioral domains of mania and to evaluate the effects of drugs using this strain. The study compared the behavior of four strains: Black Swiss, C57Bl/6, CBA/J and A/J mice in a battery of tests that included spontaneous activity; sweet solution preference; light/dark box; resident-intruder; forced-swim and amphetamine-induced hyperactivity. Based on the ‘manic-like’ behavior demonstrated by the Black Swiss strain, the study evaluated the effects of the mood stabilizers valproate and lithium and of the antidepressant imipramine in the same tests using this strain. Results indicated that lithium and valproate attenuate the ‘manic-like’ behavior of Black Swiss mice whereas imipramine had no effects. These findings suggest that Black Swiss mice might be a good choice for modeling several domains of mania and distinguishing the effects of drugs on these specific domains. However, the relevance of the behavioral phenotype of Black Swiss mice to the biology of BPD is unknown at this time and future studies will investigate molecular differences between Black Swiss mice and other strains and asess the interaction between strain and mood stabilizing treatment.
Highlights
Bipolar disorder (BPD) is a chronic and debilitating illness which includes alternate episodes of depression and mania (Sadock and Kaplan, 2002)
A number of possible approaches for the development of new models for bipolar disorder (BPD) and for mania include models based on molecular or genetic manipulations [e.g., Ralph-Williams et al, 2003; Machado-Vieira et al, 2004; Einat and Manji, 2006; Roybal et al, 2007; Malkesman et al, 2009), models based on pharmacological interventions (Antelman et al, 1998; Gould et al, 2007; Riegel et al, 2009)] and models induced by environmental stressors [e.g., sleep deprivation (Gessa et al, 1995), dominant–submissive behavior (Knapp et al, 2002; Malatynska and Knapp, 2005), swim stress (Flaisher-Grinberg and Einat, 2009b)]
STAGE 1: STRAIN DIFFERENCES IN A BATTERY OF MODELS FOR MANIA As previously reported, Black Swiss (BS) mice demonstrated a significantly higher sweet solution preference compared with all other strains and across all 4 days of the test (ANOVA: Strain, F(3,44) = 22.93, p < 0.0001, Day, F(3,132) = 42.63, p < 0.0001, Strain × Day, F(9,132) = 4.11, p < 0.001)
Summary
Bipolar disorder (BPD) is a chronic and debilitating illness which includes alternate episodes of depression and mania (Sadock and Kaplan, 2002). A model animal can be a specific species or a strain (either standard or with targeted mutation) which demonstrates behavioral or biological similarities with a disorder and may be more homologous with it (Insel, 2007; Ashkenazy et al, 2008; Flaisher-Grinberg et al, 2008; Malkesman et al, 2009) This approach was the conceptual basis for the development of strains with direct mutations to be used as models for mania (Ralph-Williams et al, 2003; Roybal et al, 2007). BS mice were found to demonstrate ‘manic-like’ increased risk-taking and reward-seeking behaviors as well as an elevated response to psychostimulants compared with C57Bl/6 mice (Hiscock et al, 2007; Flaisher-Grinberg and Einat, 2009a)
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