Summarizing the results from pathway analysis and network analysis, we were able to obtain a relatively comprehensive view about nicotine addiction (Fig 3). In such network, a number of key genes and pathways played important roles, e.g., the neurotransmitters receptor signaling transduction pathways such as dopamine receptor signaling and serotonin receptor signaling, and several intracellular signaling transduction cascades such as cAMP-mediated signaling, G-protein coupled receptor signaling and calcium signaling. The network also included several feedback loops, among which the one from N-methyl-D-aspartate subtype glutamate receptor (NMDAR) to a-amino-3-hydroxyl- 5-methylisoxazole-4-propionic acid subtype glutamate receptor (AMPAR) would be considered the shortest loops. We further observed that some loops interlinked with each other through CaM (also called CALM) and calcium/calmodulin-dependent protein kinase II (CAMKII). CaM and CAMKII both play important roles in the induction of long term potentiation and long term depression, indicating that they might make contribution to the synaptic plasticity development and they might provide clues to explain the irreversible features of nicotine addiction. In addition, we observed that mitogen-activated protein kinase (MAPK), nuclear factor of kappa light polypeptide gene enhancer
