Regulation of Dopaminergic Signaling by Drugs of Abuse

Angus Nairn, Department of Psychiatry, Pharmacology, CNNR, Yale University

The behavioral adaptations that accompany drug addiction are believed to result from both short and long-term adaptive molecular changes in brain reward centers. Moreover it is likely that exposure to drugs of abuse regulates intracellular signaling processes which in turn leads to alteration of gene expression, protein translation and post-translational modifications of proteins. As a result, repeated exposure to drugs of abuse leads to long-term, stable alterations in neuronal signaling systems that are critical for the changes in brain chemistry and structure of the addicted brain. Many studies of the effects of drugs of abuse have focused on the phosphorylation of proteins involved in glutamatergic and dopaminergic pathways, since these two neurotransmitter pathways converge in regions of the brain involved in the rewarding and cognitive effects of psychostimulants, such as the prefrontal cortex, the dorsal, and ventral striatum. As a result, much of our ongoing research, carried out as a long-term collaboration with Center member Paul Greengard, has focused on the regulation of signal transduction pathways by dopamine and glutamate in the dorsal and ventral striatum. In particular, we focus on the regulation of three of the four major neuronal serine/threonine phosphatases, PP1, PP2A and PP2B, the actions of which is controlled by a specific group of regulatory proteins. Understanding the molecular details of the signal transduction pathways controlled by dopamine and glutamate will extend our understanding of the mechanisms of action of drugs of abuse. However, a particular challenge in studies of neuronal signal transduction, which is common to all biochemical and proteomic studies of the central nervous system, is the intermixed nature and structural heterogeneity of different types of neurons. A central goal of our studies is therefore to develop methods that allow for interrogation of protein expression and regulation in different neuronal cell types, as well as in their sub-compartments, including the nucleus, mitochondria and pre- and post-synaptic compartments.