We have reviewed a growing body of evidence indicating that drug-evoked synaptic plasticity in the mesocorticolimbic DA system is common to all addictive drugs and is rooted in their common pharmacological effect of increasing DA in specific target structures. An appealing hypothesis therefore posits that drug-evoked changes in the VTA may constitute an initial permissive step for changes in the NAc and PFC, which then mediate many of the core behavioral changes that define addiction. The well-documented of the different classes of addictive drugs on other brain regions may in turn mediate specific symptoms that make the addiction to a specific drug unique. This model proposes a hierarchical system of several forms of nested drug-evoked plasticity, which in part underlie the circuit reorganization that eventually leads to a transition from thoughtful, balanced decisions to the automatic, compulsive decisions, which are a hallmark of addiction. Future studies will have to work out the functional connectivity and identify the signals orchestrating the various forms of drug-evoked plasticity. Of equal importance will be determining the basis for the individual vulnerability to develop addiction. Only with a more sophisticated understanding of these topics will mechanistically solid and clinically efficient treatments become available.
