Neuroinflammatory and Glutamatergic Mechanisms of Nicotine Seeking

Nicotine abuse and addiction represent a significant burden to public health. Nicotine, an active alkaloid in tobacco, is responsible for addiction to tobacco-containing products such as cigars, cigarettes, and vaporized liquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as the recent surge in popularity of nicotine-containing e-cigarettes, there is a great need for innovative research on the neurobiological underpinnings of nicotine addiction and relapse. Nicotine produces cellular adaptations in brain regions associated with drug reward, especially within the nucleus accumbens core (NAcore). NAcore glutamatergic mechanisms are involved in nicotine relapse, including rapid, transient potentiation of synaptic strength (t-SP; measured as increased AMPA to NMDA ratios) and accompanying glutamate receptor changes. Due to the cue dependency of smoking behavior, exposure to nicotine-associated cues is a risk factor for relapse. We and others recently found that N-acetylcysteine (NAC), an antioxidant and anti-inflammatory currently under investigation as an addiction therapeutic, appears to inhibit nicotine cue-associated t-SP and restore glial glutamate transport (GLT-1). As well, preliminary data collected during an R00 award period indicate that NAcore GLT-1 restoration is necessary for NAC to reduce nicotine seeking, and NAC inhibits expression of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα), within the NAcore. TNFα activates nuclear factor-kappa B (NF-κB) signaling and regulates learning, memory, and synaptic plasticity. Thus, in Aim 1 we propose to characterize the role of NF-κB signaling in nicotine self-administration and cued nicotine seeking. As well, this aim will determine if TNFα signaling impacts t-SP during cued nicotine relapse, and if a monoclonal antibody against TNFα can inhibit these aberrant processes. Importantly, TNFα monoclonal antibodies are used clinically for autoimmune disorders and are known to inhibit TNFα from binding to its receptor. Aim 2 will then determine the role of microglia in t-SP and nicotine seeking using chemogenetics. Interestingly, we have found that GLT-1 expression rapidly increases along with t-SP during cued nicotine seeking. It is unclear, however, if this is regulated by neuroinflammation and accompanied by astrocyte and microglial migration to the synapse during nicotine seeking. Therefore, in Aim 3 we propose to bi-directionally control microglia using chemogenetics to determine their ability to gate NAcore astrocyte-synaptic contact during nicotine seeking. In conclusion, findings from these investigations will uncover an active, dynamic role of neuroinflammatory signaling in nicotine self-administration and cue-driven nicotine relapse-associated synaptic plasticity, and broaden the scope of our current understanding of neurobiological mechanisms underlying nicotine addiction.