Additive effects of histone deacetylase inhibitors and amphetamine on histone H4 acetylation, cAMP responsive element binding protein phosphorylation and DeltaFosB expression in the striatum and locomotor sensitization in mice.

Histone deacetylase (HDAC) plays an important role in chromatin remodeling in response to a variety of neurochemical signalings and behavioral manipulations, and may be a therapeutic target for modulation of psychostimulant behavioral sensitization. In this study, we investigated the molecular interaction between histone deacetylase inhibitor (HDACi) and psychostimulant in vivo of mice after repeated treatment with the HDACi, butyric acid (BA) and valproic acid (VPA), alone or in combination with amphetamine. Repeated treatment with amphetamine produced HDACi-like effects: enhanced global histone H4 acetylation level by Western blot as well as specific histone H4 acetylation associated with fosB promoter by chromatin immunoprecipitation in the striatum. Conversely, repeated treatment with BA or VPA produced amphetamine-like effects: enhanced cAMP responsive element binding protein (CREB) phosphorylation at Ser(133) position and increased DeltaFosB protein levels in the striatum. Furthermore, co-administration of BA or VPA with amphetamine produced additive effects on histone H4 acetylation as well as CREB phosphorylation in the striatum. The interplay of HDAC and CREB was also supported by co-immunoprecipitation assays demonstrating that repeated treatment with VPA reduced the association of CREB and HDAC1 in the striatum. Finally, the additive effect of VPA/BA and amphetamine on histone H4 acetylation, phosphorylated CREB, and DeltaFosB was associated with potentiated amphetamine-induced locomotor activity. Thus, HDACi may interact additively with psychostimulants at both histone acetylation and CREB phosphorylation through the CREB:HDAC protein complex in the striatum to modulate DeltaFosB protein levels and psychomotor behavioral sensitization.