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
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 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.
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Acute and chronic drug exposures (stimulants, opioids, alcohol, nicotine) increase total cellular levels of acetylation of histones H3 and H4, apparently by unbalancing HAT and HDAC function.
“These studies have shown that acute and chronic drug exposures (stimulants, opioids, alcohol, nicotine) increase total cellular levels of acetylation of histones H3 and H4 105- 110 , apparently by unbalancing HAT and HDAC function.”
From Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention (2023) · cites this paper as [106]
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- Authors
- Shen, H.-Y., Kalda, A., Yu, L., Ferrara, J., Zhu, J., & Chen, J.-F.
- Affiliations
- Boston University (US)
- Corresponding author
- Chen, J.-F.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 157
- Issue
- 3
- Pages
- 644-655
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2080792460
- Cited by
- 91
- References
- 58
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 10 · 2020: 1 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 10 · 2013: 6 · 2012: 5
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (R01DA019362, DA19362)
- National Institute of Neurological Disorders and Stroke (R01NS041083, NS41083)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- histone deacetylase inhibitors, amphetamine, histone H4 acetylation, CREB phosphorylation, ΔFosB, striatum, locomotor sensitization, butyrate, valproic acid, chromatin remodeling, additive drug effects
- MeSH terms
- Acetylation, Amphetamine, Central Nervous System Stimulants, Animals, Corpus Striatum, Drug Interactions, Enzyme Inhibitors, Histones, Male, Mice, Inbred C57BL, Motor Activity, Phosphorylation, Time Factors, Valproic Acid, Gene Expression, Proto-Oncogene Proteins c-fos, Butyric Acid, Chromatin Immunoprecipitation, CREB-Binding Protein, Mice
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