Regulation of Synaptic Structure and Function 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 previous work, carried out as a long-term collaboration with Center member Paul Greengard, has focused on the regulation of protein phosphorylation by dopamine and glutamate in the dorsal and ventral striatum. Many of these studies have involved regulation of the serine/threonine phosphatases, PP1. Through the regulation of DARPP-32, PP1 plays a critical role in mediating the effects of drugs of abuse. Other studies have shown that PP1 is recruited to dendritic spines via an interaction with spinophilin and its homolog, neurabin, where PP1 can then dephosphorylate spine-enriched proteins, such as neurotransmitter receptors.

Several of our ongoing studies have benefited from the use of the proteomic resources and support of the NIDA Neuroproteomics Center. In future studies, we propose to (1) use protein profiling methods to study the effect of cocaine exposure on the proteins associated with the post-synaptic density; (2) study the phosphorylation and function of the Rho-GEF, LFC, which we have found to play a role in regulating the actin cytoskeleton in spines; (3) further characterize a family of substrates for protein kinase A that are enriched in striatal medium spiny neurons; (4) use both protein profiling and phosphoproteomic analysis to identify phosphoprotein substrates that are differentially regulated by PP1 isoforms.