Although the Na+-dependent plasma membrane dopamine transporter is the immediate target of cocaine, the effects of chronic exposure to cocaine are complex, wide-spread and long-lasting. Since no effective treatment is available, it is essential to develop a better understanding of the molecular, cellular and system-wide changes that lead to addiction. Structural changes at many of the synapses involved in addiction are thought to underlie these long-lived changes. Since dendritic spine morphology is largely controlled by the actin cytoskeleton, attention has turned to the pathways through which cocaine could alter the cytoskeleton. Small GTP binding proteins of the Rho family play an important role in this process and are activated by RhoGEFs and inactivated by Rho GTPase Activating Proteins. There are ~60 RhoGEFs in the human genome, and about a dozen are found in significant amounts at the PSD [16]. We have focused on one of these RhoGEFs, Kalirin, because it is essential for normal synaptic function and mice engineered to lack its major adult isoform exhibit altered responses to cocaine [12,17].
