The Epigenetics of Cocaine Addiction: An Analysis of D1 and D2 Dopamine Receptor-Expressing Neurons

Abstract

Cocaine addiction is one of the most common substance use disorders worldwide. Currently, there are no medications approved by the U.S. Food and Drug Administration to treat cocaine addiction. Repeated exposure to cocaine induces long-term changes in the brain, resulting in increased displeasure and negative moods when not taking the drug. Cocaine abuse causes persistent plasticity, altering the composition and levels of membrane receptors involved in neuronal signaling pathways. This leads to long-term, stable changes in synaptic connectivity and strength in the dopaminergic system, particularly involving the D1 and D2 Dopamine Receptor-Expressing Neurons [DRD1 and DRD2]. These two cell types comprise 95% of the NAc, a key node of the brain’s reward circuitry whose role is to translate motivation into action. Previously, there have been limited systematic or quantitative studies on the differences in structure between DRD1 and DRD2 neurons in the context of drug addiction. This paper mapped out the 3D structure of the DRD1 and DRD2 genome, identified the regions most affected by the epigenetic mechanisms of cocaine treatment, and quantified the subsequent changes in gene expression. Future experiments and studies can expand upon the results from this research to target specific regions of chromatin in DRD1 and DRD2 neurons in order to reverse the effects of cocaine abuse.