Epigenetics and psychostimulant addiction

Abstract

Chronic drug exposure alters gene expression in the brain and produces long-term changes in neural networks that underlie compulsive drug taking and seeking. Exactly how drug-induced changes in synaptic plasticity and subsequent gene expression are translated into persistent neuroadaptations remains unclear. Emerging evidence suggests that complex drug-induced neuroadaptations in the brain are mediated by highly synchronized and dynamic patterns of gene regulation. Recently, it has become clear that epigenetic mechanisms contribute to drug-induced structural, synaptic, and behavioral plasticity by regulating expression of gene networks. Here we review how alterations in histone modifications, DNA methylation, and microRNAs regulate gene expression and contribute to psychostimulant addiction with a focus on the epigenetic mechanisms that regulate brain-derived neurotrophic factor (BDNF) expression following chronic cocaine exposure. Identifying epigenetic signatures that define psychostimulant addiction may lead to novel, efficacious treatments for drug craving and relapse.

Figure 1.

Differential cocaine-induced effects at specific Bdnf promoters are mediated by distinct epigenetic mechanisms in the mPFC and VTA. (A) Cocaine selectively increases Bdnf exon IV–containing transcript levels in the mPFC. Cocaine-induced increases in mPFC Bdnf transcription are associated with increased CREB phosphorylation and histone H3 acetylation at Bdnf exon IV promoters. Furthermore, MeCP2 binding to Bdnf exon IV promoter regions is decreased following cocaine self-administration. (B) In contrast, cocaine selectively increases Bdnf exon I–containing transcript levels in the VTA. Cocaine-induced increases in VTA Bdnf transcription are associated with recruitment of CBP, an enzyme that catalyzes the addition of acetyl groups to histone proteins, and increased histone H3 acetylation at exon I–containing promoter regions. AC, acetyl group; Bdnf, brain-derived neurotrophic factor; CBP, CREB-binding protein; CRE, cAMP response element; CREB, cAMP response element binding protein; Ex IV, exon IV; Ex I, exon I; HAT, histone acetyltransferase; Me, methyl group; MeCP2: methyl-CpG-binding protein 2; P, phosphate group.