Abstract
Valproate (VPA) has recently been shown to influence the behavioral effects of psycho-stimulants. Although glycogen synthase kinase 3β (GSK3β) signaling in the nucleus accumbens (NAc) plays a key role in mediating dopamine (DA)-dependent behaviors, there is less direct evidence that how VPA acts on the GSK3β signaling in the functionally distinct sub-regions of the NAc, the NAc core (NAcC) and the NAc shell (NAcSh), during psycho-stimulant-induced hyperactivity. In the present study, we applied locomotion test after acute methamphetamine (MA) (2 mg/kg) injection to identify the locomotor activity of rats received repeated VPA (300 mg/kg) pretreatment. We next measured phosphor-GSK3β at serine 9 and total GSK3β levels in NAcC and NAcSh respectively to determine the relationship between the effect of VPA on MA-induced hyperlocomotor and changes in GSK3β activity. We further investigated whether microinjection of VPA (300 μg/0.5 μl/side, once daily for 7 consecutive days) into NAcC or NAcSh could affect hyperactivity induced by MA. Our data indicated that repeated VPA treatment attenuated MA-induced hyperlocomotor, and the effect was associated with decreased levels of phosphorylated GSK3β at Ser 9 in the NAcC. Moreover, repeated bilateral intra-NAcC, but not intra-NAcSh VPA treatment, significantly attenuated MA-induced hyperactivity. Our results suggested that GSK3β activity in NAcC contributes to the inhibitory effects of VPA on MA-induced hyperactivity.
Highlights
Bipolar disorder is a severe mental illness that affects approximately 1% of the world’s population [1]
To determine the role of glycogen synthase kinase 3β (GSK3β) activity in nucleus accumbens (NAc) sub-regions during the locomotor hyperactivity induced by MA injection, we examined the levels of phosphor-GSK3β at Ser 9 and total GSK3β by western blot in NAc core (NAcC) and NAc shell (NAcSh) respectively after the behavioral tests
The effect was associated with decreased levels of phosphorylated GSK3β at Ser9 in the NAcC but not NAcSh
Summary
Bipolar disorder is a severe mental illness that affects approximately 1% of the world’s population [1]. VPA Inhibit MA-Induced Hyperactivity via GSK3β in NAcC (VPA) has been used in the clinic for many years as mood stabilizer for bipolar disorder, the molecular mechanisms by which it exert therapeutic effects have not been fully established. The inhibitory effect of VPA on hyperlocomotor activity induced by psycho-stimulants could involve changes in functionally distinct sub-regions of the NAc, the NAc core (NAcC) and the NAc shell (NAcSh). Identification of the anatomical locus and underlying mechanisms will provide insight into the pathogenesis of mania, and may shed some light on providing novel strategies for the prevention or treatment of mania According to their distinct histochemical characteristics and hodological organization, the NAcC and NAcSh have been distinguished in the ventral striatum. Our data suggest that VAP attenuated the MA related hyperactivity, at least in part, through restoring GSK3β signaling in NAcC
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