The study of gene expression and chromatin remodeling in adult brain is made difficult by two major technical challenges. The first challenge is inherent to the structure of the brain: it is highly heterogeneous and contains many subtypes of neurons and glia, each of which are further distinguished based on connectivity and function. Thus, the cellular and molecular responses to cocaine can vary tremendously even within a small subregion of the NAc. In response to cocaine, for example, neurons which express the Gs-coupled dopamine D1 receptors in the NAc show higher levels of cAMP and its downstream consequences, while neurons expressing the Gi-coupled D2 receptors respond oppositely. There is even a small population of striatal neurons which express both D1 and D2 receptors, where they are reported to form heterooligomers that couple to Gq signaling [85], even further complicating the cellular responses to cocaine. The end result of studying tissue lysates from such a heterogeneous structure is that most of the observed effects will be very small since they are averaged together with several other, differently responding, cell types. This
