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Molecular neurobiology of nicotine addiction

Institution: University of California, Los Angeles
Investigator(s): Jim Boulter, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0136 Award: $263,298
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Scientists working in the field of drug addiction have discovered that most abused substances (or drugs) possess ‘reinforcing properties’ which are important predictors of their addiction potential. Any substance which makes us feel good (or can relieve pain or discomfort) has positive reinforcing qualities and, given the opportunity, it is likely that we would continue to take such drugs even if they were known to have long-term negative effects on our health. The repeated use of some drugs can lead to addiction, a condition characterized by compulsive drug-seeking behavior and use. Surprisingly, cigarette smoking is one of the most common forms of addictive behavior in the United States and researchers tell us that it is the ‘reinforcing properties’ of a substance called nicotine that is at the root of this compulsive behavior.

How does nicotine lead to this addictive behavior? Nicotine is one of many compounds found in tobacco that enter your lungs when tobacco leaves are smoked. From your lungs, nicotine is transported via blood circulation into your brain where nicotine delivers its pleasurable affect. While many of the details remain to be discovered, much is known about how nicotine works. First, we know that nicotine (like other drugs of abuse such as heroin, cocaine, and amphetamine) interacts directly with cells in our brain to change the way they function. Not every brain cell is affected, but those cells which do respond to nicotine have proteins on their surface (called nicotinic receptors) which bind nicotine. Second, research done during the last two decades has revealed that there is, in fact, a large family of receptor proteins in our brains which bind nicotine. Furthermore, we now know that the binding of nicotine stimulates this family of receptor proteins and that such receptor activation represents the first step in a complex process which eventually leads to addiction.

Research in our laboratory has centered on identifying the various nicotinic receptor proteins, discovering where they are expressed in the brain, and characterizing their functional role in brain cells. In this way we hope to learn how nicotine changes the physiology of brain cells and elicits such a strong, addictive behavior. In our research proposal we outlined experiments that would extend and refine our studies on this family of nicotinic receptor proteins. Specifically, we would like to know which of the many known nicotinic receptors are essential for initiating and establishing compulsive tobacco use. To answer this question we are using recombinant DNA and genetic engineering techniques to construct strains of laboratory mice each of which are missing a single nicotinic receptor protein. By comparing the genetically engineered mice to their normal litter mates we can ask: Do these altered mice still respond to nicotine? Can they eventually become addicted to nicotine? If so, do they become addicted faster, slower, or at the same rate as normal mice? Finally, do these mice experience ‘withdrawal symptoms’ if nicotine treatment is withheld? The answers to these questions will provide the foundation for identifying individual nicotinic receptors, specific brain cells, and circuits which are most sensitive to nicotine exposure. Understanding how nicotine works and what it does to our brains is an essential first step in helping public health workers, scientists, and physicians design effective strategies for eliminating tobacco use and preventing the devastation of tobacco-related disease among habitual smokers.
Publications

Pharmacological and immuniological characterization of alpha2 nicotine acetylcholine receptors (nAChRs) in mouse brain.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Whiteaker P, Drapeau JA, Brown RWB, Brennan RJ, Collins AC, Lindstrom JM, Boulter J ART
Yr: 2004 Vol: Nbr: Abs: Pg:

Genetic engineering of a nAChR alpha2 subunit gene 'knockout' mouse.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Byun J, Brennan RJ, Boulter J ABS
Yr: 2004 Vol: Nbr: Abs: Pg: