Anatomical Basis for Nicotine Addiction

PROJECT SUMMARY (See instructions): Despite the necessary role of dopamine in nicotine reinforcement, it is not sufficient to explain the complexity of addiction. Additional processes, particularly the ability of cues associated with nicotine exposure to develop control over behavior, are essential for ongoing drug seeking. Both human subjects and rodents experience reward-enhancement when exposed to nicotine. This has led to the idea that one of the primary factors driving nicotine addiction is its ability to potentiate the value of other appetitive stimuli and to accelerate cue-reward learning. The major achievement arising from this grant is the discovery of a VT A-to-VP GABA circuit and a MS-to-BLA ACh circuit that increase responding for rewards and reward-paired cues. We have now published manuscripts on characterization and manipulation of these novel, potentially interacting, circuits, as well as on proteomic approaches to identify intracellular pathways downstream of nAChRs in the VTA that contribute to cellular and morphological plasticity following nicotine administration. Our new and updated Aims will expand on this progress by identifying the role of nAChRs in these circuits, exploring cholinergic inputs to the VTA-to-VP GABA neurons, identifying nicotine-dependent proteomic changes in BLA, and determining whether these pathways interact to promote cue-reward behaviors. Together, these proposed studies will go beyond initial steps of nicotine reward mediated through DA signaling to identify circuits and signaling pathways involved in the ability of nicotine to potentiate rewarding responses, processes that likely contribute to long-term susceptibility to nicotine addiction and relapse.