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AMPA Receptors and Extinction of Nicotine-Seeking Behavior

Institution: University of California, San Diego
Investigator(s): Manoranjan Dsouza, M.D., Ph.D.
Award Cycle: 2010 (Cycle 19) Grant #: 19FT-0045 Award: $135,000
Subject Area: Nicotine Dependence
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Tobacco smoking continues to be a significant and preventable cause of illnesses and death all over the world. Further smoking, which is attributed partly to the addictive properties of nicotine contained in tobacco, is a disorder that is characterized by an inability on part of smokers to quit smoking and repeated returns to smoking (relapse) among those who manage to quit smoking for a while. It is reported that only 3% of USA smokers who try to quit smoking manage to remain abstinent for 6 months, while most relapse within the first month. This high rate of relapse among abstinent smokers is attributed to associations between the rewarding effects of nicotine and environmental stimuli associated with smoking. Further, nicotine enhances the rewarding effects of stimuli associated with tobacco smoking. To prevent relapse to smoking in smokers who previously quit smoking there is a need to enhance processes, such as extinction. Extinction is a process that involves new learning and helps to decrease behaviors that previously led to the administration of nicotine. To enhance extinction learning in tobacco smokers, research should first identify substances in the brain that are involved in extinction of nicotine-seeking behavior which will subsequently help in the development of therapies that will enhance extinction learning, maintain abstinence and prevent relapse of nicotine-seeking behavior. Previous studies from our laboratory and that of others have shown that repeated nicotine administration over a period of time, alters communication between sites in the brain involved in the rewarding effects of drugs of abuse, including nicotine. Further, we have found that this altered communication is mediated by a substance in the brain (neurotransmitter) called glutamate. This altered glutamatergic communication results in increased drug-seeking and the development of a nicotine dependence state characterized by unpleasant and aversive effects upon termination of nicotine administration. It is suggested that extinction training, contributes to decreased nicotine-seeking by reversing this altered glutamatergic communication that results from repeated intake of nicotine. The alterations in glutamatergic transmission are likely mediated by alterations in expressions of certain type of protein (receptors) in the brain called amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate (AMPA) receptors. These receptors play a critical role in nicotine dependence and are also believed to play an important role in learning processes such as extinction. In the proposed work, we will assess the role of AMPA receptors in extinction of nicotine-seeking behavior. The proposed studies will involve first assessing the changes in expression of AMPA receptor subunits and their phosphorylated forms after repeated nicotine intake and extinction of nicotine-seeking behavior in different brain sites involved in the rewarding effects of nicotine. Next, we will attempt to improve extinction training by increasing the expression AMPA receptor subunits (GluR1 and GluR2) in subdivisions of a brain region called the nucleus accumbens (core vs. shell) using viral vectors. The nucleus accumbens was chosen because a significant body of literature indicates that one of its subdivisions, the shell, plays an important role in extinction while the core plays an important role in drug-seeking behavior. Finally, we will attempt to improve extinction of nicotine-seeking behavior by administering a drug [4-[2-(phenylsulphonyllamino) ethylthio]-2,6-difluorophenoxyacetamide (PEPA)] that increases activity of AMPA receptors. In summary, the proposed studies will use state-of-the-art techniques to understand the role of AMPA receptors in extinction of nicotine-seeking behavior. These results will not only enhance our understanding of extinction of nicotine-seeking behavior but more importantly will facilitate the discovery and development of medications that will prevent smokers from reinitiating their smoking habit. Overall, this work will help to reduce illnesses and deaths associated with tobacco smoking which is one of the primary research areas of the TRDRP.
Publications

Neuronal mechanisms underlying development of nicotine dependence: Implications for_x000d_ new smoking-cessation treatments.
Periodical: Addiction Research and Theory Index Medicus:
Authors: DSouza MS & Markou A ART
Yr: 2011 Vol: 6 Nbr: 1 Abs: Pg: 4-16

Effects of mGluR5 antagonist MPEP microinjections in the nucleus accumbens and ventral tegmental area on nicotine and food self-administration
Periodical: Neuropharmacology Index Medicus:
Authors: DSouza MS and Markou A ART
Yr: 2011 Vol: 61 Nbr: 8 Abs: Pg: 1399-405

Schizophrenia and tobacco smoking comorbidity: nAChR agonists in the treatment of_x000d_ schizophrenia-associated cognitive deficits.
Periodical: Neuropharmacology Index Medicus:
Authors: DSouza MS & Markou A ART
Yr: 2012 Vol: 62 Nbr: 3 Abs: Pg: 1564-73

The metabotropic glutamatergic 2/3 receptor agonist LY379268 blocked nicotine-induced increases in the nucleus accumbens shell dopamine in rats in the presence of nicotine-associated context in rats
Periodical: Neuropsychopharmacology Index Medicus:
Authors: D'Souza MS, Liechti ME, Ramirez AM, Kuczenski R and Markou A ART
Yr: 2011 Vol: 36 Nbr: 10 Abs: Pg: 2111-2124

The metabotropic glutamate receptor 5 antagonist 2-methyl-6- (phenylethynyl) pyridine (MPEP) microinfusions in the nucleus accumbens shell and ventral tegmental area attenuate the reinforcing effects of nicotine in rats
Periodical: Neuropharmacology Index Medicus:
Authors: DSouza MS and Markou A ART
Yr: 2011 Vol: 61 Nbr: 8 Abs: Pg: 1399-1405

N-acetylcysteine decreased nicotine self-administration and cueinduced reinstatement of nicotine-seeking in rats.
Periodical: Psychopharmacology Index Medicus:
Authors: Ramirez A, DSouza MS and Markou A ART
Yr: 2013 Vol: 225 Nbr: 2 Abs: Pg: 473-82