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

Abstract

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.