Tobacco use is the greatest preventable cause of death, cancer, and illness in the United States. Some smoking cessation interventions are effective, but the majority of individuals who stop smoking relapse within a year. A better understanding of the mechanisms underlying vulnerability to relapse can help pave the way for more effective treatments. Mark Namba and Dr. Cassie Gipson-Reichardt in the Neurobiology and Behavior in Addiction Lab at Arizona State University use an animal model of cue-induced relapse to study neurobiological substrates underlying relapse vulnerability. Under this model, rats are trained to self-administer nicotine, the primary active alkaloid in tobacco. Then, rats are placed into extinction training for several days, in which self-administration responses no longer produce nicotine or nicotine-paired cues. Following extinction, cue-induced nicotine relapse is tested by allowing the rats to respond in the presence of cues that had previously been paired with nicotine delivery. In an ongoing study, Namba and Dr. Gipson-Reichardt are using this model to examine whether drug-induced neuroinflammation may underlie vulnerability to nicotine relapse. Chronic nicotine self-administration is associated with enduring alterations in glutamatergic plasticity within the nucleus accumbens core, including dysregulation of glial glutamate transport. The nuclear factor kappa B (NF-κB) pathway mediates drug-induced neuroinflammation and is a key regulator of synaptic plasticity. Notably, little is known about NF-κB’s role in cue-induced nicotine relapse. To address this limitation, Namba and Dr. Gipson-Reichardt are using a herpes virus gene transfer strategy to express several forms of IκB kinase (IKK) to bi-directionally modulate activation of downstream NF-κB. Additionally, they and others have demonstrated that N-acetylcysteine, an antioxidant and glutamatergic agent, inhibits cue-induced nicotine relapse and are currently examining whether NF-κB signaling underlies its therapeutic efficacy. Preliminary results suggest that NF-κB signaling mediates cue-induced nicotine relapse. Specifically, inhibition of NF-κB inhibits cue-induced reinstatement, whereas activation of NF-κB drives reinstatement and blocks the attenuating effect of N-acetylcysteine on reinstatement. Overall, these findings are significant because they highlight the potential role for neuroimmune signaling as a modulatory mechanism that regulates glutamatergic synaptic plasticity and subsequent drug-seeking behavior, thus revealing a new avenue for the development of novel pharmacotherapeutics aimed at reducing the risk of nicotine relapse. Dr. Gipson-Reichardt has been a member of CPDD since 2013; she currently serves on the Program Committee. Dr. Holtyn has been a member of CPDD since 2013; she currently serves on the Animals in Research Committee. By August Holtyn, Ph.D., Animals in Research Committee Chair *This work was supported by the National Institutes of Health Grant DA036569 and -S1.
