1. ¹Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, Worcester, MA, USA
2. ²Program in Neuroscience, University of Massachusetts Graduate School of Biomedical Sciences, Worcester, MA, USA
3. ³Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
4. ⁴Department of Psychiatry, Vanderbilt University, Nashville, TN, USA

Correspondence: Dr S Akbarian, Associate Professor in Psychiatry, University of Massachusetts Medical School, Brudnick Neuropsychiatric Research Institute, 303 Belmont Street, Worcester, MA 01604, USA. Tel: +508 856 2674; Fax: +508 856 3937; E-mail: Schahram.Akbarian@umassmed.edu

Received 31 October 2007; Revised 21 January 2008; Accepted 21 January 2008; Published online 20 February 2008.

Abstract

Chromatin remodeling, including histone modification, is involved in stimulant-induced gene expression and addiction behavior. To further explore the role of dopamine D₁ receptor signaling, we measured cocaine-related locomotor activity and place preference in mice pretreated for up to 10 days with the D₁ agonist SKF82958 and/or the histone deacetylase inhibitor (HDACi), sodium butyrate. Cotreatment with D₁ 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 D₁ 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 D₁ agonist and HDACi. Collectively, these findings imply that D₁ receptor-regulated histone (phospho)acetylation and gene expression in reward circuitry is differentially regulated in a region-specific manner. Given that the combination of D₁ agonist and HDACi enhances cocaine-related sensitization and reward, the therapeutic benefits of D₁ receptor antagonists and histone acetyl-transferase inhibitors (HATi) warrant further investigation in experimental models of stimulant abuse.