This revised competing renewal application for 2R01DA011946 (requesting funding for years 12-16) is in response to PA-10-268 that promotes research to """"""""understand the neurobiological mechanisms underlying all phases of drug addiction, including....relapse, as well as the effects of pharmacological treatments aimed at curbing substance use. An understanding of the neurobiological mechanisms underlying drug addiction can help to identify targets for prevention and treatment interventions"""""""". Tobacco smoking, attributed partly to the addictive properties of nicotine, is a chronic relapsing disorder The majority of smokers who attempt to quit relapse within one month. Conditioned motivational effects of smoking-related cues contribute to this chronic vulnerability to relapse amongst abstinent smokers. Thus, blockade of the motivational impact of smoking- related cues or enhancement of extinction learning and memory using pharmacological treatments are possible strategies to prolong abstinence in smokers. Glutamate plays a critical role in the development of nicotine dependence. Importantly, studies suggest that enhancing glutamatergic transmission during extinction training can facilitate extinction of fear and conditioned drug-associated memories, while exposure to drug- associated cues enhances glutamatergic transmission resulting in reinstatement of drug seeking. Based on these findings, the overall hypothesis of this project is that enhancing glutamate transmission during extinction will facilitate extinction learning and decrease subsequent cue-induced nicotine seeking. In contrast, blockade of increased glutamate transmission in response to nicotine-associated cues will attenuate reinstatement of nicotine seeking.
Specific Aim 1 will assess the effects of blockade of glutamatergic transmission, by targeting either the AMPA or metabotropic glutamate 2 (mGlu2) or metabotropic glutamate 5 (mGlu5) receptors, on cue- induced reinstatement of nicotine seeking.
Specific Aim 2 will assess the effects of pharmacological treatments that subtly increase glutamate transmission via either AMPA, mGlu5 or mGlu2/3 receptors on extinction of nicotine seeking and subsequent cue-induced reinstatement of nicotine seeking. Different brain regions and circuits mediate extinction and cue-induced reinstatement of drug seeking. Thus, it is hypothesized that the nucleus accumbens (NAcc) shell plays an important role in extinction learning, while the NAcc core is more involved in drug seeking. Hence, Specific Aim 3 will assess the effects of viral-vector mediated increased expression of AMPA receptor subunits (GluR1 and GluR2) in the NAcc core and shell on extinction training and subsequent cue-induced reinstatement of nicotine seeking. Using a combination of state-of-the-art behavioral, pharmacological, anatomical and molecular techniques, the proposed studies will promote our understanding of the neuromechanisms and neuroanatomical sites mediating extinction of nicotine seeking, and cue-induced reinstatement of nicotine seeking. The findings will identify pharmacological approaches for the prevention of relapse, and thus promote abstinence from the harmful tobacco smoking habit.

Public Health Relevance

Tobacco dependence, which is partly attributed to the highly addictive properties of nicotine, is a significant public health problem. The investigation of potential pharmacological approaches to enhance extinction and decrease nicotine-seeking is a highly innovative approach to the development of treatments for nicotine dependence. The discovery of such pharmacological approaches to the treatment of nicotine dependence will have a big impact on public health by assisting people in their attempts to quit and remain abstinent from tobacco smoking.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
High Priority, Short Term Project Award (R56)
Project #
Application #
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Lynch, Minda
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Li, Xia; D'Souza, Manoranjan S; NiƱo, Ana M et al. (2016) Attenuation of nicotine-taking and nicotine-seeking behavior by the mGlu2 receptor positive allosteric modulators AZD8418 and AZD8529 in rats. Psychopharmacology (Berl) 233:1801-14
Der-Avakian, Andre; Barnes, Samuel A; Markou, Athina et al. (2016) Translational Assessment of Reward and Motivational Deficits in Psychiatric Disorders. Curr Top Behav Neurosci 28:231-62
Justinova, Zuzana; Le Foll, Bernard; Redhi, Godfrey H et al. (2016) Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys. Psychopharmacology (Berl) 233:1791-800
Hall, F Scott; Der-Avakian, Andre; Gould, Thomas J et al. (2015) Negative affective states and cognitive impairments in nicotine dependence. Neurosci Biobehav Rev 58:168-85
Li, Xia; Markou, Athina (2015) Metabotropic Glutamate Receptor 7 (mGluR7) as a Target for the Treatment of Psychostimulant Dependence. CNS Neurol Disord Drug Targets 14:738-44
Stoker, Astrid K; Marks, Michael J; Markou, Athina (2015) Null mutation of the ?2 nicotinic acetylcholine receptor subunit attenuates nicotine withdrawal-induced anhedonia in mice. Eur J Pharmacol 753:146-50
Chan, Ming-Huan; Tsai, Yi-Ling; Lee, Mei-Yi et al. (2015) The group II metabotropic glutamate receptor agonist LY379268 reduces toluene-induced enhancement of brain-stimulation reward and behavioral disturbances. Psychopharmacology (Berl) 232:3259-68
Stoker, Astrid K; Markou, Athina (2015) Neurobiological Bases of Cue- and Nicotine-induced Reinstatement of Nicotine Seeking: Implications for the Development of Smoking Cessation Medications. Curr Top Behav Neurosci 24:125-54
Li, Xia; Semenova, Svetlana; D'Souza, Manoranjan S et al. (2014) Involvement of glutamatergic and GABAergic systems in nicotine dependence: Implications for novel pharmacotherapies for smoking cessation. Neuropharmacology 76 Pt B:554-65
Dhanya, Raveendra-Panickar; Sheffler, Douglas J; Dahl, Russell et al. (2014) Design and synthesis of systemically active metabotropic glutamate subtype-2 and -3 (mGlu2/3) receptor positive allosteric modulators (PAMs): pharmacological characterization and assessment in a rat model of cocaine dependence. J Med Chem 57:4154-72

Showing the most recent 10 out of 24 publications