Chronic drug exposure also causes significant changes of histone modification. Histone acetylation is known to be associated with activated gene expression. Chronic cocaine exposure was shown to inhibit the function of Hdac5, a histone deacetylase, in mouse NAc (Renthal et al., 2007). Activation of dopamine D1 receptor induced upregulation of histone acetylation at the promoters of tyrosine hydroxylase (Th) and brain-derived neurotrophic factor (Bdnf) genes in mouse NAc and the expression of the two genes (Schroeder et al., 2008). There was a reported association in mice between histone H3 acetylation-activated transcription of addiction-related genes, such as CamkII-α and the motivation for cocaine (L. Wang et al., 2010). In mice chronically administered amphetamine, the Δ-FosB-mediated responses were also found to involve recruiting Hdac1 to its target gene promoters (Renthal et al., 2008). Inhibition of histone deacetylase reduced behavioral sensitization to morphine in mice (Jing et al., 2011). Alteration of histone methylation also plays important roles in neuronal adaptation of addicted brain. Repeated cocaine administration in mice was shown to repress the expression of lysine dimethyltransferase G9a, resulting in decrease of histone lysine 9 dimethylation (H3K9me2) in NAc (Maze et al., 2010).
