Tobacco smoking is a leading cause of premature death. Nicotine, the primary active alkaloid in tobacco, is generally accepted as being responsible for maintaining smoking behavior. As well, chronic use of addictive drugs has been found to produce enduring neuroadaptations in the corticostriatal brain circuitry involved in the plasticity of learning and behavior. Existing evidence suggests that a disruption in glutamate homeostasis (a balance between extrasynaptic and synaptic neuronal glutamate concentrations that regulate synaptic plasticity) within the NA is a contributing mechanism to this chronic relapse vulnerability. It is thought that dynamic drug-induced changes in this pathway impair the normal processing of information that contributes to the adaptive regulation of motivated behavior. It is unclear, however, to what extent nicotine self-administration and the reinstatement of nicotine-seeking behavior causes alterations in glutamate homeostasis. I am proposing to use an animal model of nicotine-seeking to determine if changes in glutamate homeostasis during nicotine withdrawal and reinstated nicotine-seeking are similar to those that occur during cocaine withdrawal and cocaine-seeking. Specifically, I hypothesize that nicotine self-administration will change protein levels associated with glutamate homeostasis, as well as synaptic release of NA glutamate and dopamine during cue-induced reinstatement. The proposed research will determine the relationship, if any, between nicotine and cocaine on alterations in glutamate homeostasis as an underlying neurobiological mechanism of relapse to different drugs of abuse. As well, the proposed research has the potential to reveal novel mechanisms of nicotine addiction, and thus may aid in targeting more effective pharmacological treatment. In the process, I will be trained in Western blot analysis, in vivo microdialysis involving no-net flux following nicotine self-administration and extinction training, as well as cu-induced reinstatement of nicotine-seeking behavior in rats.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DA033690-02
Application #
8491758
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Babecki, Beth
Project Start
2012-06-01
Project End
2013-10-31
Budget Start
2013-06-01
Budget End
2013-10-31
Support Year
2
Fiscal Year
2013
Total Cost
$21,746
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Gipson, Cassandra D; Kupchik, Yonatan M; Kalivas, Peter W (2014) Rapid, transient synaptic plasticity in addiction. Neuropharmacology 76 Pt B:276-86
Stankeviciute, Neringa M; Scofield, Michael D; Kalivas, Peter W et al. (2014) Rapid, transient potentiation of dendritic spines in context-induced relapse to cocaine seeking. Addict Biol 19:972-4
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
Gipson, Cassandra D; Reissner, Kathryn J; Kupchik, Yonatan M et al. (2013) Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Proc Natl Acad Sci U S A 110:9124-9