Changes in striatal dopamine transporters in bipolar disorder and valproate treatment

Abstract

Background: Previous studies suggested that a disturbance of the dopamine system underlies the pathophysiology of bipolar disorder (BD). In addition, the therapeutic action of medications for treating BD, such as valproate (VPA), might modulate dopamine system activity, but it remains unclear. Here, we aimed to investigate the role of the striatal dopamine transporter (DAT) in BD patients and in social defeat (SD) mice treated with VPA.

Methods: We enrolled community-dwelling controls (N = 18) and BD patients (N = 23) who were treated with VPA in a euthymic stage. The striatal DAT availabilities were approached by TRODAT-1 single photon emission computed tomography. We also established a chronic SD mouse model and treated mice with 350 mg/kg VPA for 3 weeks. Behavioral tests were administered, and striatal DAT expression levels were determined.

Results: In humans, the level of striatal DAT availability was significantly higher in euthymic BD patients (1.52 ± 0.17 and 1.37 ± 0.23, p = 0.015). Moreover, the level of striatal DAT availability was also negatively correlated with the VPA concentration in BD patients (r = -0.653, p = 0.003). In SD mice, the expression of striatal DAT significantly increased (p < 0.001), and the SD effect on DAT expression was rescued by VPA treatment.

Conclusions: The striatal DAT might play a role in the pathophysiology of BD and in the therapeutic mechanism of VPA. The homeostasis of DAT might represent a new therapeutic strategy for BD patients.

Keywords: Bipolar disorder; dopamine transporter; striatum; valproate.

Figure 1.

The correlation of the VPA concentration and the level of striatal DAT availability in BD patients. (A) The representative brain image of striatal DAT availability in a BD patient and a control participant. (B) The level of total striatal DAT availability in plots between BD and controls. The effect size was 0.76. (C) The VPA concentration was significantly negatively correlated with the total level of striatal DAT availability in BD patients (r = −0.653, p = 0.003). Abbreviations: BD, bipolar disorder; VPA, valproate; DAT, dopamine transporter.

Figure 2.

The experimental design of the chronic SD stress mouse model. (A) The scheme showed the experimental design of the chronic SD stress mouse model. (B) After SD, the social interaction ratio was decreased in SD mice group (N = 16) than that in control (N = 16). (C) The immobility of FST was increased in SD mice group than that in control (p < 0.0001). Data were presented as mean ± SEM (N = 16 per group). ****p < 0.0001. Abbreviations: SD, social defeat; VPA, valproate.

Figure 3.

The DAT expression at striatum in chronic SD stress mouse model treated with VPA. (A) Representative western blot reveals the expression levels of DAT at striatum in mice. (B) Quantification of western blot data. Each group contained eight independent samples. The result indicated that the DAT level at striatum significantly increased in SD group compared to control group (indicated all of data sub-grouped by control (N = 16) or SD mice group (N = 16), p < 0.001). Considering the effect of 3-week VPA treatment, the DAT expression significantly decreased in SD + VPA group compared with the SD + saline, while there was not different between control + VPA and control + saline (p = 0.230). Moreover, although the reduced level of DAT expression in SD + VPA group was significantly higher than that in control + VPA (p < 0.05), the levels were not significantly different between the SD + VPA and control + saline groups. Data were expressed as mean ± SEM (N = 8 per group). *p < 0.05, ***p < 0.001 Abbreviations: SD, social defeat; VPA, valproate; DAT, dopamine transporter.