Nicotine abuse and addiction represents a large health liability. Indeed, cigarette smoking-related illness results in an estimated 6,000,000 deaths per year worldwide, yet 20% of adults currently smoke, and among those who attempt to quit, >90% relapse. Nicotine, the primary active alkaloid in tobacco, is self-administered by animals and produces cellular adaptations in brain regions associated with drug reward, such as the nucleus accumbens. Due to the cue dependency of smoking behavior, exposure to nicotine-associated cues is a risk factor for relapse. Here, I examine the role of glial glutamate transport and NMDA receptors in nicotine relapse vulnerability. I have found that nucleus accumbens core glutamatergic mechanisms are involved in nicotine relapse, including increased synaptic strength (measured as increased spine diameter and AMPA currents) and accompanying protein changes (including a decrease in the glial glutamate transporter, GLT1, and increases in the AMPA subunit GluA1 and NMDA subunit GluN2B). During the proposed award period, I will explore the mechanisms mediating cued nicotine reinstatement and a possible neuron-glia interaction underlying relapse vulnerability. In the K99 aims, I propose to functionally characterize nicotine-mediated down-regulation of GLT1, and to determine its role in reinstated nicotine seeking. To do this, I will learn glutamate uptake and whole cell patch clamp electrophysiology strategies, as well as employ my Western blot and intracranial microinjection skills I acquired during my F32 NRSA. I will also use antisense vivo morpholinos and ceftriaxone to examine the impact of up- or down-regulated GLT1 on reinstatement of nicotine seeking. I will employ these techniques during the R00 period to further characterize the role of GluN2B in cue-reinstated nicotine seeking, and to explore a potential neuron-glia interaction mediating nicotine relapse. During the R00 period, I will electrophysiologically determine if the upregulated GluN2B receptors I found in nicotine-extinguished animals are extrasynaptic and necessary for cued nicotine seeking. I will accomplish this with an innovative set of techniques including a coagonist degredation procedure using whole cell patch clamp, and administration of siRNA constructs to downregulate GluN2B in nicotine-extinguished animals to determine if normalizing this protein inhibits cued nicotine seeking in nicotine-extinguished animals. This will indicate a key role of glutamate overflow and activation of extrasynaptic NMDA receptors in relapse vulnerability. Next, I will determine if restoring GluN2B with siRNA or GLT1 with ceftriaxone indirectly restores GLT1 or GluN2B, respectively, indicating a neuron-glia interaction in cue-induced nicotine relapse. Finally, I will examine if restoring GluN2B or GLT1 prevents the rapid, transient synaptic plasticity I previously found during cued nicotine reinstatement. These experiments have the potential to reveal novel neurobiological mechanisms of nicotine addiction, and could contribute to the development of novel therapeutic options aimed at reversing nicotine-induced neurobiological alterations.

Public Health Relevance

Drug addiction is associated with long-lasting brain changes that cause heightened relapse vulnerability, even after extended drug abstinence. The proposed research has the potential to reveal novel neurobiological mechanisms of nicotine addiction, and could contribute to the development of novel therapeutic options aimed at reversing nicotine-induced alterations.

National Institute of Health (NIH)
Career Transition Award (K99)
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Special Emphasis Panel (ZDA1)
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Sorensen, Roger
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Medical University of South Carolina
Schools of Medicine
United States
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Gipson, Cassandra D (2016) Treating Addiction: Unraveling the Relationship Between N-acetylcysteine, Glial Glutamate Transport, and Behavior. Biol Psychiatry 80:e11-2
Gipson, C D; Olive, M F (2016) Structural and functional plasticity of dendritic spines - root or result of behavior? Genes Brain Behav :
Garcia-Keller, C; Kupchik, Y M; Gipson, C D et al. (2016) Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration. Mol Psychiatry 21:1063-9
McClure, Erin A; Gipson, Cassandra D; Malcolm, Robert J et al. (2014) Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs 28:95-106