It is thought that nicotine is one of the main psychoactive ingredients in tobacco smoke that leads to habitual tobacco smoking in humans. Nicotine induces pleasurable euphoric-like effects and also enhances the effects of other rewarding stimuli (i.e., reward facilitation). Further, adaptations induced by chronic nicotine administration result in deficits in brain reward function and somatic signs during nicotine withdrawal. These three effects associated with nicotine consumption (i.e., pleasurable effects of acute nicotine, nicotine- induced facilitation of other rewards, and the aversive nicotine withdrawal syndrome) are all hypothesized to provide important sources of motivation that perpetuate the deadly tobacco smoking habit. The goals of the proposed project are threefold.
Specific Aim 1 will attempt to identify specific nicotinic acetylcholine receptor (nAChR) subunits critically involved in the primary reinforcing effects of nicotine.
Specific Aim 2 will attempt to identify nAchR subunits critically involved in the reward enhancing effects of acute nicotine. Finally, Specific Aim 3 will attempt to identify specific nAChR subunits which are critically involved in the brain reward function deficits and somatic signs associated with nicotine withdrawal. The proposed studies will be carried out in wildtype mice and genetically modified mice in which a7 or ?4 nAChR subunits have been null mutated or in which a 4 nAChR subunits have been rendered hypersensitive to nicotine (a7-/-, ?4-/-, and Leu9'Ala mice, respectively). These subunits have been selected because their localization implicates them in the effects of nicotine investigated in the proposed studies. To identify nAChR subunits critical to the various aspects of nicotine dependence, intravenous nicotine self-administration and intracranial self-stimulation (ICSS) procedures will be utilized. Nicotine self-administration and nicotine- induced lowering of ICSS thresholds will serve as measures of the reinforcing effects of nicotine and nicotine-induced facilitation of reward, respectively. Elevations of ICSS thresholds (i.e., reward deficits) and increased somatic signs of withdrawal during spontaneous nicotine withdrawal will serve as measures of the affective and somatic components of nicotine withdrawal, respectively. These studies will determine whether nAchRs containing the a7, ?4 and/or a4 subunits are critically involved in mediating effects of nicotine that are hypothesized to be crucial motivating factors in maintaining the tobacco smoking habit. Full nicotine dose-response functions will be generated. Future work will use additional mutant mice to investigate the potential role of other nAchR subunits in the same phenomena. Relevance: Improved understanding of the neurobiological substrates that underlie the rewarding effects of nicotine, the reward-enhancing effects of nicotine and the aversive effects of nicotine abstinence will provide insights into the sources of motivation that result in persistent use of tobacco in humans, and is likely to lead to new and improved behavioral and pharmacological treatments to assist smokers in quitting. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023209-02
Application #
7404564
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (02))
Program Officer
Lynch, Minda
Project Start
2007-04-10
Project End
2012-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$264,968
Indirect Cost
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Stoker, Astrid K; Markou, Athina (2013) Unraveling the neurobiology of nicotine dependence using genetically engineered mice. Curr Opin Neurobiol 23:493-9
Stoker, Astrid K; Olivier, Berend; Markou, Athina (2012) Involvement of metabotropic glutamate receptor 5 in brain reward deficits associated with cocaine and nicotine withdrawal and somatic signs of nicotine withdrawal. Psychopharmacology (Berl) 221:317-27
Hall, F Scott; Markou, Athina; Levin, Edward D et al. (2012) Mouse models for studying genetic influences on factors determining smoking cessation success in humans. Ann N Y Acad Sci 1248:39-70
Semenova, Svetlana; Contet, Candice; Roberts, Amanda J et al. (2012) Mice lacking the ?4 subunit of the nicotinic acetylcholine receptor show memory deficits, altered anxiety- and depression-like behavior, and diminished nicotine-induced analgesia. Nicotine Tob Res 14:1346-55
Chan, Ming-Huan; Chung, Shiang-Sheng; Stoker, Astrid K et al. (2012) Sarcosine attenuates toluene-induced motor incoordination, memory impairment, and hypothermia but not brain stimulation reward enhancement in mice. Toxicol Appl Pharmacol 265:158-65
D'Souza, Manoranjan S; Markou, Athina (2012) Schizophrenia and tobacco smoking comorbidity: nAChR agonists in the treatment of schizophrenia-associated cognitive deficits. Neuropharmacology 62:1564-73
Stoker, Astrid K; Olivier, Berend; Markou, Athina (2012) Role of ?7- and ?4-containing nicotinic acetylcholine receptors in the affective and somatic aspects of nicotine withdrawal: studies in knockout mice. Behav Genet 42:423-36
Stoker, Astrid K; Markou, Athina (2011) Withdrawal from chronic cocaine administration induces deficits in brain reward function in C57BL/6J mice. Behav Brain Res 223:176-81
Contet, Candice; Whisler, Kimberly N; Jarrell, Holly et al. (2010) Patterns of responding differentiate intravenous nicotine self-administration from responding for a visual stimulus in C57BL/6J mice. Psychopharmacology (Berl) 212:283-99
Markou, Athina; Paterson, Neil E (2009) Multiple motivational forces contribute to nicotine dependence. Nebr Symp Motiv 55:65-89

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