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Regulatory genes of nicotine adaptation in C.elegans

Institution: University of California, San Diego
Investigator(s): Suchitra Jagannathan, BSc, MSc, PhD
Award Cycle: 2003 (Cycle 12) Grant #: 12FT-0048 Award: $70,000
Subject Area: Nicotine Dependence
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Tobacco use has resulted in major health problems worldwide, and cigarette smoking is the largest avoidable cause of death and disability in the United States. Extensive efforts at reducing the numbers of tobacco consumers have been launched by both governmental and private agencies. However, there is strong emotional and social attachment to the ‘tobacco habit’, referred to as ‘psychological dependence.’ Thus, smokers attempting to abstain, may have to overcome both psychological and physical dependence on tobacco, which immediately presents a formidable task for many individuals. Nicotine is the major component sustaining tobacco addiction. Nicotine interacts with proteins called receptors in the brain, which release the chemical acetylcholine upon the binding of the drug and receiving a stimulus; hence the term nicotinic acetylcholine receptors. These receptors in general, are present in either muscle or in the nervous system. Extensive work has been done thus far through the use of various biological techniques, to understand the functioning of these receptors, but its real physiological role is still elusive. This is because, the molecular and neurobiological mechanisms underlying drug addiction in general, and nicotine addiction in particular, are poorly understood. Further understanding of these mechanisms is possible by correlating molecular processes, directly with behavior. For instance, use of nicotine over long periods of time, is found to cause adaptive changes in the activity and even number of nicotinic receptors in the brain. These changes then result in the acquisition of nicotine tolerance, appearance of withdrawal symptoms, and then an increase in drug seeking behavior.

One convenient method to further elucidate the processes underlying such long-term responses, is by using a genetically tractable worm called Caenorhabditis elegans as an experimental model system. C.elegans is transparent and lives in the soil. It can also be easily grown under laboratory conditions. Importantly, every cell in this animal has been mapped in terms of its location. Although the nervous system is simple in organization, its function is complex, and it does resemble the human system in terms of the repertoire of molecules involved. Using classical genetics, the more recently developed ‘genomics-based’ tools, and other behavioral studies possible on this worm, molecules that regulate the function of the nicotinic acetylcholine receptor and promote nicotine adaptation will be determined. The insights gained from these studies will prove useful for the identification of novel proteins that participate in nicotine addiction in the human brain.