Nicotine addiction is a manifold process that involves dysregulated executive control, reward processing and negative affect. Preclinical models reveal that self-administration of nicotine produces an imbalance in corticostriatal glutamate transmission that mediates cue-induced reinstatement to nicotine seeking. Prior research suggests that N-acetylcysteine (NAC), a modified cysteine chain that regulates glial glutamate and normalizes cocaine-induced synaptic plasticity, may attenuate perceived smoking reward and smoking behavior. Crucially however, our preclinical data suggests NAC may be most effective under conditions of abstinence as a relapse prevention aid. Thus, pairing a smoking cessation medication (Varenicline: VRN) that promotes abstinence, with a relapse prevention aid (NAC), may produce greater cessation outcomes than either treatment alone. The overarching goal of this proposal is to use clinical and preclinical neuroscience to investigate limbic-striatal and corticostriatal circuits involved in nicotine addiction and determine the valueof VRN+NAC for normalizing circuitry function and treating nicotine addiction. Smokers interested in quitting will be randomized to one of four placebo (PBO) controlled conditions to examine the individual and combined effects of VRN and NAC over 4-weeks. Following 1-week of treatment, participants will be contingently reinforced for 3 days of smoking abstinence and undergo an fMRI scan. Participants will be followed over the next 3-weeks of treatment and clinically relevant behaviors will be assessed. Relations between fMRI measures and clinical variable will be explored. In our analog preclinical studies that use the same treatment groups as the clinical studies, we will employ an optogenetic strategy to examine the efficacy of VRN+NAC at inhibiting synaptic plasticity in prelimbic (PL) and basolateral amygdala (BLA) inputs to the nucleus accumbens produced during cue-induced nicotine seeking.

Public Health Relevance

Preclinical and Human models suggest that nicotine addiction disrupts neural function in amygdala-striatal network involved in negative reinforcement and a corticostriatal network (PFC-VS) involved in regulating reward. The overarching goal of this proposal is to utilize clinical and preclinical neuroscience to investigate plasticity in amygdala- striatal and corticostriatal circuits involved in nicotine addiction and determine the value of combined Varenicline and N- acetylcysteine for normalizing circuitry changes and treating nicotine addiction. This research represents an important next step in translational research that will provide novel insights into the neurobiological and neurocognitive basis of smoking reinforcement and relapse vulnerability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA038700-05
Application #
9753199
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Kautz, Mary A
Project Start
2015-09-15
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
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
29407
Tomko, Rachel L; Gray, Kevin M; Oppenheimer, Stephanie R et al. (2018) Using REDCap for ambulatory assessment: Implementation in a clinical trial for smoking cessation to augment in-person data collection. Am J Drug Alcohol Abuse :1-16
Tomko, Rachel L; Jones, Jennifer L; Gilmore, Amanda K et al. (2018) N-acetylcysteine: A potential treatment for substance use disorders. Curr Psychiatr 17:30-36, 41-42, 55
Froeliger, Brett; McConnell, Patrick A; Bell, Spencer et al. (2017) Association Between Baseline Corticothalamic-Mediated Inhibitory Control and Smoking Relapse Vulnerability. JAMA Psychiatry 74:379-386
Tomko, Rachel L; Bountress, Kaitlin E; Gray, Kevin M (2016) Personalizing substance use treatment based on pre-treatment impulsivity and sensation seeking: A review. Drug Alcohol Depend 167:1-7
Scofield, M D; Heinsbroek, J A; Gipson, C D et al. (2016) The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis. Pharmacol Rev 68:816-71
Bentzley, Jessica P; Tomko, Rachel L; Gray, Kevin M (2016) Low Pretreatment Impulsivity and High Medication Adherence Increase the Odds of Abstinence in a Trial of N-Acetylcysteine in Adolescents with Cannabis Use Disorder. J Subst Abuse Treat 63:72-7
Squeglia, Lindsay M; Gray, Kevin M (2016) Alcohol and Drug Use and the Developing Brain. Curr Psychiatry Rep 18:46
Kalivas, Benjamin C; Kalivas, Peter W (2016) Corticostriatal circuitry in regulating diseases characterized by intrusive thinking. Dialogues Clin Neurosci 18:65-76