Over a billion men, women and children worldwide smoke, and tobacco continues to be the largest single cause of premature death in developed countries. Nicotine, the main addictive component of tobacco, produces the neurophysiological, motivational and behavioural changes associated with nicotine addiction. Understanding the neuropharmacological, anatomical and behavioural underpinnings of the psychoactive effects of nicotine is key for the identification of new therapeutical targets and the development of new drugs against nicotine dependence. This proposal stems from recent data in the lab that pinpoint a novel mechanism of action for nicotine. We now show that the drug can change maturation and turnover of scaffolding proteins and neurotransmitter receptors by blocking proteasomal activity. Our data indicate that nicotine's effects on the proteasome occur via both nAChR-mediated and nAChR- independent mechanisms. These results provide a mechanism that could explain some of the effects of nicotine, including the drug-induced changes in protein levels, and nAChR upregulation. This exploratory grant will continue the characterization of the proteasome/nicotine interaction with both in vivo and in vitro mechanisms. To determine whether nicotine's influence on the proteasome is one of the mechanisms underlying the pharmacological effects of nicotine we will examine the behavioral effects of nicotine in mice in which proteasomal function is perturbed by proteasomal inhibitors or the inducible knockout of a proteasomal component. Other biochemical and pharmacological experiments will provide information on the nature of the nicotine/proteasome interaction. The investigation of nicotine's influence on the proteasome is important not only for the effects of nicotine on the brain but it will also provide new insights on the effects of tobacco on tissues and organs that do not express nAChRs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA024385-02
Application #
7564774
Study Section
Special Emphasis Panel (ZDA1-MXS-M (31))
Program Officer
Wu, Da-Yu
Project Start
2008-02-01
Project End
2010-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
2
Fiscal Year
2009
Total Cost
$153,500
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
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
McLaughlin, Ian; Dani, John A; De Biasi, Mariella (2015) Nicotine withdrawal. Curr Top Behav Neurosci 24:99-123
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Rezvani, Khosrow; Baalman, Kelli; Teng, Yanfen et al. (2012) Proteasomal degradation of the metabotropic glutamate receptor 1? is mediated by Homer-3 via the proteasomal S8 ATPase: Signal transduction and synaptic transmission. J Neurochem 122:24-37
Paolini, Michael; De Biasi, Mariella (2011) Mechanistic insights into nicotine withdrawal. Biochem Pharmacol 82:996-1007
Rezvani, Khosrow; Teng, Yanfen; De Biasi, Mariella (2010) The ubiquitin-proteasome system regulates the stability of neuronal nicotinic acetylcholine receptors. J Mol Neurosci 40:177-84
Rezvani, Khosrow; Teng, Yanfen; Pan, Yaping et al. (2009) UBXD4, a UBX-containing protein, regulates the cell surface number and stability of alpha3-containing nicotinic acetylcholine receptors. J Neurosci 29:6883-96