Schroeder FA, Penta KL, Matevossian A, Jones SR, Konradi C, Tapper AR et al. Drug-induced activation of dopamine D(1) receptor signaling and inhibition of class I/II histone deacetylase induce chromatin remodeling in reward circuitry and modulate cocaine-related behaviors. Neuropsychopharmacology 33: 2981-2992

Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.83). 03/2008; 33(12):2981-92. DOI: 10.1038/npp.2008.15
Source: PubMed

ABSTRACT Chromatin remodeling, including histone modification, is involved in stimulant-induced gene expression and addiction behavior. To further explore the role of dopamine D(1) receptor signaling, we measured cocaine-related locomotor activity and place preference in mice pretreated for up to 10 days with the D(1) agonist SKF82958 and/or the histone deacetylase inhibitor (HDACi), sodium butyrate. Cotreatment with D(1) agonist and HDACi significantly enhanced cocaine-induced locomotor activity and place preference, in comparison to single-drug regimens. However, butyrate-mediated reward effects were transient and only apparent within 2 days after the last HDACi treatment. These behavioral changes were associated with histone modification changes in striatum and ventral midbrain: (1) a generalized increase in H3 phosphoacetylation in striatal neurons was dependent on activation of D(1) receptors; (2) H3 deacetylation at promoter sequences of tyrosine hydroxylase (Th) and brain-derived neurotrophic factor (Bdnf) in ventral midbrain, together with upregulation of the corresponding gene transcripts after cotreatment with D(1) agonist and HDACi. Collectively, these findings imply that D(1) receptor-regulated histone (phospho)acetylation and gene expression in reward circuitry is differentially regulated in a region-specific manner. Given that the combination of D(1) agonist and HDACi enhances cocaine-related sensitization and reward, the therapeutic benefits of D(1) receptor antagonists and histone acetyl-transferase inhibitors (HATi) warrant further investigation in experimental models of stimulant abuse.

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Available from: Schahram Akbarian, Aug 22, 2015
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    • "A wide variety of environmental stimuli that induce Bdnf transcription have been demonstrated to drive increased acetylation of histones selectively at induced Bdnf promoters in physiologically relevant brain regions. Stimuli that have been shown to induce histone acetylation in conjunction with Bdnf transcription include seizure (Tsankova et al. 2004; Huang et al. 2002), membrane depolarization (Chen et al. 2003a; Martinowich et al. 2003), antidepressant treatment (Tsankova et al. 2006), cocaine administration (Kumar et al. 2005), forced cocaine abstinence (Sadri-Vakili et al. 2010), dopamine D1 receptor agonist administration (Schroeder et al. 2008), and extinction of conditioned fear (Bredy et al. 2007). Among the molecular mechanisms that mediate steady-state changes in histone acetylation at Bdnf, the histone acetyltransferase CBP has been shown to be recruited to the CREB binding site of Bdnf promoter IV in an activity-dependent manner (Hong et al. 2008), and the histone deacetylase HDAC2 has been found to be preferentially associated compared to HDAC1 with Bdnf promoters I and II in vivo (Guan et al. 2009). "
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    • "The mRNA levels of tyrosine hydroxylase were found to increase in the ventral midbrain upon exposure to a D1 agonist and the HDAC inhibitor, sodium butyrate, in cocaine-treated mice. This was determined to be the result of chromatin remodeling through H3 acetylation at the tyrosine hydroxylase promoter and the BDNF promoter of these regions (Schroeder et al. 2008). One of the most widely studied transcription factors implicated in the epigenetic changes caused by drug abuse is ΔFOSB, the expression of which is increased in the chronic presence of drugs of abuse. "
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