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
AuthorsSchroeder, Frederick Albert
Penta, Krista L.
Jones, Sara R.
Konradi, Christine L.
Tapper, Andrew R.
Student AuthorsFrederick Schroeder
UMass Chan AffiliationsTapper Lab
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute
KeywordsBrain; Chromatin Assembly and Disassembly; Cocaine; Histone Deacetylase Inhibitors; Receptors, Dopamine D1
Medicine and Health Sciences
Neuroscience and Neurobiology
MetadataShow full item record
AbstractChromatin 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.
Neuropsychopharmacology. 2008 Nov;33(12):2981-92. Epub 2008 Feb 20. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/32903