Valproate Reverses Mania-Like Behavior of Clock(delta19) Mouse and Alters Monoamine Neurotransmitters Metabolism in the Hippocampus

BACKGROUND: Mice with a deletion at exon 19 of the circadian locomotor output cycles Kaput gene (Clock(delta19)) exhibit mania-like behavior and have been one of the most common animal models for bipolar disorder (BD). The predictive validity of the Clock(delta19) was investigated via studies using lithium previously. Determination of effects of other mood stabilizers on Clock(delta19) mouse would be helpful for better understanding of the mechanism underlined. METHODS: Wildtype (WT) and Clock(delta19) mice were treated with saline (n = 10 for WT and n=10 for Clock(delta19)) or valproate (VPA) (n = 10 for WT and n=10 for Clock(delta19)) for 10 days. The hyperactivity, anxiety-like behaviors and depression-like behaviors were tested. The concentration of monoamine neurotransmitters and their metabolites in the hippocampus of saline or VPA treated WT and Clock(delta19) mouse (n = 8 for each) were also determined. RESULTS: VPA can reverse hyperactivity, lower level of anxiety-like and depression-like behaviors of the Clock(delta19) mouse. Clock(delta19) mouse exhibited lower levels of serotonin (5-HT) and dopamine (DA) in right hippocampus compared to WT mouse. Chronic VPA treatment did not affect the levels of 5-HT and DA, but can reduce the level of levodopa (L-DOPA) in the right hippocampus of Clock(delta19) mouse. CONCLUSION: Our results indicated that chronic VPA treatment can reverse the mania-like behaviors of the Clock(delta19) mouse and further consolidate the validity of the Clock(delta19) mouse as a model of BD. Monoamine neurotransmitters and their metabolites in the hippocampus are partly regulated by mutation of the Clock gene or VPA treatment.