Future studies will have to identify the “master signals” that control this hierarchical organization between VTA and NAc and test whether similar mechanisms control the circuit remodeling in later stages of the “spiral”. Will chronic drug exposure eventually affect transmission in the substantia nigra compacta (SNc) and the dorsal striatum? One study implicated the recruitment of these dorsal parts of the dopamine system in cocaine-seeking habits by demonstrating that the surgical disconnection of the spiral via a lesion of the NAc core, blocked the development of cocaine seeking in rats (Belin and Everitt, 2008). Thus, the spiral appears to be engaged sequentially during the development of addiction. Drug-evoked synaptic plasticity in various parts of the mesoorticolimbic system may constitute the underlying cellular correlate confirming the hypothesis that “staged neuroplasticity” underlies the disease (Kalivas and O’Brien, 2008). A model of the mesocorticolimbic circuitry that is subject to drug-evoked synaptic plasticity is emerging (Fig. 4). While this model is based on a decade’s work, it is apparent that many questions regarding the anatomical connections and precise cellular mechanisms remain unanswered.
