Valproate robustly increases Sp transcription factor-mediated expression of the dopamine transporter gene within dopamine cells.

Several lines of evidence suggest that valproate, a drug used in the treatment of mania and bipolar disorders, epilepsies, and addictions, may modulate dopamine transporter (DAT) function, yet the effects of valproate on DAT gene expression have not been directly assessed. Utilizing a human dopaminergic cell line and rat midbrain dopamine (DA) neurons in organotypic culture, we found that valproate increased endogenous DAT gene expression in a concentration- and time-dependent manner. Given previous data demonstrating that members of the specificity protein (Sp) family of transcription factors are strong trans-activators of DAT gene transcription, we investigated the Sp-dependence of valproate effects. Valproate-induced transcription of a DAT reporter construct was significantly attenuated by coexpression of a dominant negative form of Sp, mutation of a Sp-responsive cis-element, or expression in a Sp-null cellular background (SL-2 cells). Valproate significantly altered Sp protein abundance in both dopaminergic model systems employed. In summary, valproate treatment significantly increased DAT gene expression in a Sp transcription factor-dependent manner. Some of valproate's therapeutic effects may involve activation of DAT gene expression.