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CENTURY
Yale University
School of Medicine
SAC-203
Connecticut
Mental Health Center
34 Park Street
New Haven, CT 06519

Phone:
203-974-7591

Fax:
203-974-7606

E-mail:
infocentury@yale.edu

CENTURY/TTURC Press Release

New Haven, Conn. - Researchers have long suspected that nicotine addiction happens, in part, because nicotine changes the brain with repeated use. Those changes might be why some smokers find it hard to quit, because the brain adapts to nicotine use in a way that produces pleasurable feelings. Also, nicotine-induced changes might prompt addicted smokers to crave a cigarette when they are exposed to certain cues, such as driving to work or being in a bar.

Prolonged nicotine use causes neural plasticity, changes in the way neurons communicate with one another. Why, exactly, this happens is still something of a mystery. But researchers have new insight that might help eventually solve that puzzle, thanks to Dr. Darlene H. Brunzell, Ph.D., a postdoctoral associate with Dr. Marina Piccotto's lab in the Yale School of Medicine's Department of Psychiatry. Dr. Brunzell's findings were published in the March 2003 issue of the Journal of Neurochemistry.

Dr. Brunzell is part of the Center for Nicotine and Tobacco Use Research at Yale (CENTURY) and the Transdisciplinary Tobacco Use Research Center (TTURC), which is part of CENTURY. Dr. Brunzell studies the effects of nicotine exposure on molecular and neurochemical changes within neurons. One goal of the Yale TTURC is to link these intracellular changes to behaviors associated with addiction in an effort to find new targets for pharmacological interventions in smokers.

Dr. Brunzell recently examined the extracellular regulated protein kinase (ERK) pathway to find out if it might play a role in the way the brain learns to like nicotine. She decided to study the ERK pathway because it has been shown in vitro to be stimulated by nicotine, and in animals to be involved in brain changes that underlie learning.

To simulate human nicotine intake, Dr. Brunzell administered nicotine in sweetened water to C57Bl/6J mice, a strain that is known to like drugs of abuse. She found several changes in molecules in the ERK pathway that were specific to chronic exposure. One particularly interesting finding was a profound decrease in the active form of the transcription factor CREB (cyclic AMP regulated binding protein) in the nucleus accumbens. The nucleus accumbens is the area of the brain that deals with motivation, rewards and is generally implicated in drug addiction. This decrease in CREB activation has also been seen with chronic exposure to cocaine and alcohol, and could contribute to ongoing smoking behavior.

Other findings include
* CREB phosphorylation was increased in the prefrontal cortex following chronic nicotine exposure and in the ventral tegmental area during nicotine withdrawal,
* total and phosphorylated ERK decreased in the amygdala following chronic nicotine exposure, but ERK phosphorylation increased in the prefrontal cortex,
* tyrosine hydroxylase levels increased in both the amygdale and prefrontal cortex, which supports the hypothesis that increased catecholaminergic tone contributes to nicotine reinforcement.

"Overall, these results support a role for ERK and CREB activity in neural plasticity associated with nicotine dependence," Dr. Brunzell said in the study.

As part this study, Dr Brunzell collaborated with with the CENTURY/TTURC laboratory core. Her work with Research Assistant Sarah Pihonak and Dr. Peter Jatlow, from the lab, showed that levels of the nicotine metabolite cotinine in acute and chronic nicotine drinkers are comparable to heavy smokers.

For more information, please see: Brunzell, D.H., Russell, D.S. and Picciotto, M.R. In vivo nicotine treatment regulates mesocorticolimbic CREB and extracellular regulated kinase signaling in C57B1/6J mice. Journal of Neurochemistry. 2003. 84, 1431-1441.

CENTURY and TTURC were created to help people quit smoking. The focus of the research at Yale is smokers who have the greatest need for help, those who cannot quit or have trouble doing so. One of the primary goals of the initiative is to encourage and support research that integrates theories and methods from different disciplines.

TTURC was created with a grant from the National Institute on Drug Abuse (NIDA), the National Cancer Institute (NCI) and grants from The Robert Wood Johnson Foundation. Yale TTURC is one of seven centers around the country conducting a wide variety of transdisciplinary tobacco-related research. The other participating centers are Brown University, University of California at Irvine, University of Minnesota, University of Pennsylvania, Georgetown University, University of Southern California, and University of Wisconsin.

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NIDA¹s mission is to bring the power of science to bear on drug abuse and addiction. This charge has two critical components: The first is the strategic
support and conduct of research across a broad range of disciplines. The second is to ensure the rapid and effective dissemination and use of the results of that
research to significantly improve drug abuse and addiction prevention, treatment and policy.

The National Cancer Institute (NCI) is part of the National Institutes of Health (NIH), one of eight agencies that make up the Public Health Service in the Department of Health and Human Services. The NCI, established under the National Cancer Act of 1937, is the Federal Government¹s principal agency for cancer research and training. The National Cancer Act of 1971 broadened the scope and responsibilities of the NCI and created the National Cancer Program.

The Robert Wood Johnson Foundation, based in Princeton, N.J., is the nation¹s largest philanthropy devoted exclusively to health issues. Its mission is to improve the health and health care of all Americans. One of the Foundation¹s grant-making priorities is to reduce the personal, social and economic harm caused by abuse of substances such as tobacco, alcohol and illicit drugs.