In this study, we provide evidence that chronic treatment of the common mood stabilizer, VPA, elicits robust induction of Par-4, which significantly impacts DRD2-mediated signaling. Furthermore, the induction mechanism involves dynamic chromatin remodeling in the Par-4 promoter regions and indicates that part of the mood stabilizing efficacy of VPA is mediated by changes in DRD2-mediated signaling processes.
Evidence for a link between the dopamine system and mood disorders has been consistently reported. For example, anhedonia and amotivation commonly seen in mood disorder patients can be reasonably explained by deficits in dopamine circuits 
. In addition, the cerebrospinal fluid from depression patients who committed suicide often contains lower levels of dopamine metabolites 
. When animals are exposed to chronic mild stress, a behavioral paradigm that induces a depressive state, a decrease in the surface expression of DRD2 in the nucleus accumbens occurs, which can be reversed by chronic administration of antidepressants 
. Moreover, the immobility of experimental animals in Porsolt's forced swim test was reduced by D2-like dopamine receptor agonists 
. Importantly, impaired DRD2-mediated signaling by functional defects in the Par-4 protein has been associated with depression-like behavior in animal models 
. Consistent with this, one report showed that the Par-4/DRD2 signaling pathway in the striatum was modified by stress-induced depressive behavior through a non-methylation mechanism 
. Moreover, a recent postmortem study showed that Par-4 protein levels were decreased by 31% and 67% in the temporal cortices of bipolar disorder and major depression patients, respectively, without significant decreases in the DRD2 levels 
. Thus, our study not only further supports that the deregulation of dopamine signaling is involved in the pathogenesis of mood disorders, but also suggests that transcriptional upregulation may participate in the mechanism responsible for VPA-mediated mood stabilization.
The clinical effects of mood stabilizers and antidepressants are known to take a relatively long time to be achieved, which suggests the involvement of long lasting changes in the cellular environment. Chromatin remodeling has been proposed as a plausible mechanism to explain the delayed but enduring effect of mood stabilizers. In particular, VPA is known to harbor HDAC inhibitory activity that exerts an enduring impact on the chromatin state. In this study, we demonstrated that chronic VPA-associated alterations of DRD2 signaling may result from changes in chromatin states, which enhance the transcription of the Par-4 gene. It is especially noteworthy that Par-4 mRNA and protein accumulation did not increase until after several hours of treatment, which suggests a potential mechanism to explain the delayed clinical effect of VPA in human patients.
Lithium, another first line medication for bipolar disorder, has overlapping but distinct mechanisms with VPA as a mood stabilizer. For example, lithium mediates GSK-3β inhibition, which may be linked to neuroprotective effects against glutamate-induced toxicity 
. Furthermore, the co-treatment of lithium and HDAC inhibitors shows a synergistic neuroprotective effect, suggesting the GSK-3β pathway as a common target for the therapeutic effect of lithium 
. However, while lithium is known to directly inhibit GSK-3β, the effect of VPA on the GSK-3β pathway appears inconsistent depending on the experimental settings, hinting at the mechanistically distinct activities of VPA and lithium 
. Interestingly, in our study, Par-4 protein levels were not effectively elevated by lithium. Thus, the result suggests that the modulation of the dopamine signaling pathway by Par-4 induction might be a unique process mediating the therapeutic efficacy of VPA, which is distinct from the mechanisms of action of other mood stabilizers.