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

doi:10.1016/j.neuroscience.2008.09.019

Neuroscience

Volume 157, Issue 3, 2 December 2008, Pages 644-655

https://doi.org/10.1016/j.neuroscience.2008.09.019 Get rights and content

Abstract

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 Ser¹³³ position and increased ΔFosB 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 ΔFosB 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 ΔFosB protein levels and psychomotor behavioral sensitization.

Section snippets

Animals, drug treatments and locomotor activity

All experiments were performed in accordance with Boston University Medical Center and NIH guidelines on the ethical use of animals. The number of animals used and their suffering was minimized in all cases. Male C57BL/6 mice (Jackson Laboratory, Bar Harbor, MA, USA; weight, 25–30 g) were habituated to the testing environment 4 days prior to behavioral testing. Horizontal locomotor activities were assessed using an activity cage system (San Diego Instruments, San Diego, CA, USA). Mice were

Repeated co-treatment with HDACi and amphetamine increases histone H4 acetylation in the striatum

One of our major goals in this study was to assess the effect of HDACi on molecular changes (p-CREB and ΔFosB) in association with amphetamine-induced behavioral sensitization. We selected VPA and BA for testing based on two factors: (1) their reported ability to enter the CNS to produce neurochemical and behavioral changes in mice (Ferrante et al 2003, Jeong et al 2003, Ryu et al 2003, Ren et al 2004), and (2) their shared action of HDACi but with otherwise different pharmacological profiles.

Discussion

This study provides several lines of in vivo evidence for additive interactions between HDACi and amphetamine at both the molecular and behavioral levels: First, repeated treatment with amphetamine produced HDACi-like effects: global increase in histone H4 acetylation detected by Western blot as well as a specific fosB promoter-associated hyperacetylation of H4 in the striatum by ChIP assay. Second, HDACi (BA and VPA) induced two molecular changes in the striatum, CREB phosphorylation and ΔFosB

Conclusion

In summary, this report provides strong in vivo evidence for the additive interaction between HDACi and amphetamine, possibly through the HDAC:protein complex association in the striatum. On one hand, amphetamine functions like HDACi to enhance general H4 acetylation and specific fosB promoter-associated H4 hyperacetylation in the striatum. On the other hand, HDACi produces characteristic molecular changes of amphetamine, including CREB phosphorylation and ΔFosB expression in the striatum.

Acknowledgments

This work was supported by NIH grants DA19362 and NS41083 and the Bumpus Foundation (J.-F.C.). The authors thank Yumei Wang for technical assistance with chromatin immunoprecipitation and Catherine Wei for proofreading of the manuscript.

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¹: These authors contributed equally to this work.

²: Present address: Department of Nephrology, Daping Hospital and Research Institute of Surgery, The Third Military Medical University, 10 Changjiangzhi Road, Chongqing, 400042, PR China (H.-Y. Shen); Department of Pharmacology, University of Tartu, Ravila 19, EE-51014 Tartu, Estonia (A. Kalda).

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

Abstract

Section snippets

Animals, drug treatments and locomotor activity

Repeated co-treatment with HDACi and amphetamine increases histone H4 acetylation in the striatum

Discussion

Conclusion

Acknowledgments

Curr Opin Pharmacol

Neuron

FEBS Lett

Dev Biol

J Biol Chem

Cell

Neuron

FEBS Lett

Methods

Behav Brain Res

Cell

Neuron

Neuron

J Biol Chem

Prog Neurobiol

Ageing Res Rev

J Biol Chem

Brain Res

Brain Res

Methods

Neurosci Lett

Region-directed phototransfection reveals the functional significance of a dendritically synthesized transcription factor

Nat Methods

Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice

J Neurosci

Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex

Nat Struct Biol

Regulation of cocaine reward by CREB

Science

Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5

J Neurochem

Chronic Fos-related antigens: stable variants of deltaFosB induced in brain by chronic treatments

J Neurosci

Epigenetic mechanisms and gene networks in the nervous system

J Neurosci

Chromatin remodeling and neuronal response: multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons

J Cell Sci

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