Nicotine addiction is a major worldwide medical and social problem that continues to escalate. Affective and somatic symptoms associated with nicotine withdrawal contribute to the difficulty in quitting tobacco use. While current therapies for smoking cessation are helpful, none can claim a very high rate of success. Therefore, there is a great need for a better understanding of the behavioral and biological factors underlying nicotine withdrawal. Stress and anxiety play an important role in the maintenance of nicotine abuse. Anxiety promotes cigarette use and it is also one of the symptoms of withdrawal, making tobacco abstinence more difficult. This application builds on the observation that lack of (4* or ?5* nicotinic acetylcholine receptors (nAChRs) significantly reduces somatic signs of withdrawal and reduces anxiety-like responses. (4* and ?5* nAChRs are prominently expressed in the medial habenula/interpeduncu?lar nucleus (MHb/IPN) axis. The habenula is a source of negative reward signals and participates in a wide array of behaviors including anxiety and stress. We postulate that (4* and ?5* nAChRs in the MHb/IPN axis are in a key position to influence the mesolimbic dopamine system during nicotine withdrawal. Control mice and mice lacking the (4 or the ?5 nAChR subunit will be chronically treated with nicotine delivered in the drinking water, and withdrawal will be precipitated by injection of the nAChR antagonist mecamylamine. First, we will examine the role of (4* and ?5* nAChRs on anxiety-related responses during withdrawal using a battery of behavioral paradigms. Second, we will ask which manifestations of nicotine withdrawal are directly influenced by the (4* and ?5* nAChRs expressed in the MHb/ IPN axis. In those experiments, lentiviral vectors will be used to either re-express (4 or ?5 in the MHb or the IPN of (4 and ?5 null mice or to knock down the levels of ?5 and ?4 in MHb and IPN of wild type mice.

Public Health Relevance

Stress, Anxiety, and Nicotine Withdrawal Public health relevance Our studies will take advantage of genetically engineered mice and novel genetic techniques, and will combine behavioral analysis, molecular biology, and pharmacology to study the complex interaction between nicotine, stress and anxiety. The goal is to identify possible pharmacological targets that will help develop effective smoking-cessation aids.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017173-07
Application #
7894866
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Volman, Susan
Project Start
2003-09-30
Project End
2013-04-30
Budget Start
2010-08-01
Budget End
2013-04-30
Support Year
7
Fiscal Year
2010
Total Cost
$345,375
Indirect Cost
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
McLaughlin, Ian; Dani, John A; De Biasi, Mariella (2017) The medial habenula and interpeduncular nucleus circuitry is critical in addiction, anxiety, and mood regulation. J Neurochem 142 Suppl 2:130-143
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Teng, Yanfen; Rezvani, Khosrow; De Biasi, Mariella (2015) UBXN2A regulates nicotinic receptor degradation by modulating the E3 ligase activity of CHIP. Biochem Pharmacol 97:518-530
Perez, E E; De Biasi, M (2015) Assessment of affective and somatic signs of ethanol withdrawal in C57BL/6J mice using a short-term ethanol treatment. Alcohol 49:237-43
Perez, Erika; Quijano-Cardé, Natalia; De Biasi, Mariella (2015) Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine. Neuropsychopharmacology 40:2327-36
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Dani, John A; De Biasi, Mariella (2013) Mesolimbic dopamine and habenulo-interpeduncular pathways in nicotine withdrawal. Cold Spring Harb Perspect Med 3:

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