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Neurobiological substrates of nicotine addiction

Institution: University of California, San Diego
Investigator(s): Athina Markou, Ph.D.
Award Cycle: 2006 (Cycle 15) Grant #: 15RT-0022 Award: $419,503
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Tobacco smoking, which is attributed primarily to the addictive properties of nicotine contained in tobacco smoke, continues to be a worldwide health problem and leads to several hundred thousand deaths per year in the USA alone. The cost to society is significant in terms of health problems that frequently lead to death, medical costs and human suffering. It has been projected that by the year 2020 tobacco will become the largest single health problem worldwide, leading to approximately 8.4 million deaths annually. Considering that the risk for developing diseases associated with tobacco smoking is reduced when smoking is stopped, there is much incentive to conduct high quality biomedical research to develop more effective prevention and cessation strategies for tobacco smoking than currently available. The present grant application addresses the large societal and medical problem of tobacco smoking by proposing the conduct of biomedical research that will help us better understand the factors that lead to the development of dependence on nicotine and tobacco smoking, and the adaptations that occur in the brain with chronic exposure to nicotine. The first set of studies will systematically explore the factors that lead to the development of nicotine dependence and withdrawal. Such factors include the dose of nicotine, duration of daily exposure to nicotine, total number of days that the subject is exposed to nicotine, whether nicotine is self-administered or given by the experimenter to the subject and whether nicotine is infused continuously or administered as brief pulses similar to the way people smoke tobacco. These studies will promote our understanding of the factors and patterns of nicotine administration that lead to nicotine dependence and withdrawal symptoms upon cessation of nicotine administration, and thus will allow the design of interventions to prevent the development of nicotine dependence in people that have recently initiated smoking, such as adolescents and young adults. The second set of studies will investigate the adaptations and changes that occur in the function of the brain reward systems with the development of nicotine dependence. These adaptations and changes lead not only to dependence on tobacco smoking and the aversive symptoms of withdrawal experienced upon smoking cessation, but also to relapse to smoking despite the individual’s best efforts. Relapse to tobacco smoking after a period of abstinence is a common problem, with 80% of individuals relapsing to tobacco smoking within one year after they quit. Thus, it is important to invest research resources in understanding and preventing relapse to tobacco smoking, and thus limit the harmful effects of smoking in society. In the brain, nicotine produces its effects by attaching to and “activating” specific sites called receptors, and more specifically, the nicotinic acetylcholine receptors. The activation of nicotinic acetylcholine receptors, in some brain sites, leads to increased release of the endogenous substance glutamate, which in turn attaches to and activates N-methyl-D-aspartate glutamate receptors. The present studies will investigate how different regimens of exposure to nicotine affect the function of these two types of receptors that are located in the brain’s reward circuits and modulate the perception of the reward value of stimuli, and whether the changes in the function of these receptors are long-lasting and persistent. Additional studies will also assess how different nicotine exposure regimens alter the numbers of nicotinic acetylcholine receptors in different areas of the brain. Long-lasting and persistent adaptations in the function of these brain receptors may make the individual more susceptible to relapse to tobacco smoking. Taken together, these studies will provide us with valuable information that will help us design effective intervention and treatment programs that will involve both behavioral and pharmacological interventions, to prevent people from developing dependence to tobacco smoking, or quit smoking and remain abstinent, and thus avoid the detrimental effects of tobacco smoking on health.
Publications

Chronic bupropion partially attenuated the reinforcement-enhancing, but not reinforcing, effects of self-administered nicotine and enhanced motivational properties of a nicotine-associated conditioned stimulus in rats.
Periodical: Nicotine and Tobacco Research Index Medicus:
Authors: Paterson, N.E., Balfour, D.J., and Markou, A. ART
Yr: 2008 Vol: Nbr: Abs: Pg:

Role of the glutamatergic system in nicotine dependence: Implications for the discovery and development of new pharmacological smoking cessation therapies.
Periodical: CNS Drug Discovery Index Medicus:
Authors: Liechti, M.E. and Markou, A. ART
Yr: 2008 Vol: Nbr: Abs: Pg:

Spontaneous nicotine withdrawal potentiates the effects of stress in rats.
Periodical: Neuropsychopharmacology Index Medicus:
Authors: Jonkman, S., Risbrough, V.B., Geyer, M.A. and Markou, A. ART
Yr: 2008 Vol: Nbr: Abs: Pg:

Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence.
Periodical: Behavioral Pharmacology Index Medicus:
Authors: Markou, A., Liechti, M.E., Lhuillier, L. and Kaupmann, K. ABS
Yr: 2007 Vol: 18 Nbr: (Suppl. 1) Abs: Pg: S88-S89

GABAb receptor positive modulators decrease nicotine self-administration in rats.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Vlachou, S., Paterson, N.E., Guery, S., Froestl, W.F., Kaupmann, K. and Markou,A. ABS
Yr: 2007 Vol: 273 Nbr: 123 Abs: Pg:

Metabotropic glutamate 2/3 (mGlu2/3) receptors in the ventral tegmental area and the nucleus accumbens mediate nicotine reward and exhibit downregulated function after chronic nicotine self-administration.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Liechti, M.E., Lhuillier, L, Kaupmann, K., and Markou, A. ABS
Yr: 2007 Vol: 679 Nbr: 97 Abs: Pg:

GABAb receptor positive modulators decrease nicotine self-adminstraton in rats.
Periodical: Biochemical Pharmacology Index Medicus:
Authors: Vlachou, S., Paterson, N.E., Guery, S., Froestl, W.F., Kaupmann, K. and Markou, A. ABS
Yr: 2007 Vol: SMA 44 Nbr: Suppl. Abs: Pg:

Psychopharmacological models focusing on stimulus bound behaviour.
Periodical: European Neuropsychopharmacology Index Medicus:
Authors: Markou, A. ABS
Yr: 2008 Vol: Nbr: Abs: Pg: S35-S36

Glutamate and the reinforcing effects of nicotine.
Periodical: European Neuropsychopharmacology Index Medicus:
Authors: Liechti, M., Kuczenski, R. and Markou, A. ABS
Yr: 2008 Vol: Nbr: Abs: Pg: S56