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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. - The Yale Transdisciplinary Tobacco Use Research Center (TTURC) has been awarded about $9.5 million to continue its studies through September 2009. A complete list of projects, with descriptions, is available on this page.

The Yale Tobacco Center is one of seven research centers that will be funded over the next five years by the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the National Cancer Institute (NCI). The seven research centers will receive about $12 million a year, with about $1.7 to $2 million of that going to Yale each year.

The Yale TTURC, in its quest to find new pharmacological and behavioral solutions for smokers, will build upon several breakthrough developments that suggest specific factors make it harder for some people to quit.

During the initial round of TTURC funding, Yale researchers identified biological factors that contribute to smoking relapse, engaged in a collaboration that resulted in the development of a new radiotracer that allows researchers to take pictures of where nicotine acts in the brain, and found that low doses of the drug naltrexone resulted in reduced weight gain by those who are trying to quit.

The Yale TTURC's new round of studies will find solutions for subgroups of smokers who find it particularly hard to quit. Those subgroups include women, people who drink, people who are worried about their weight, and people who are depressed and/or anxious . While these factors have been studied independently in the past, the Yale TTURC renewal will examine how the factors interact with one another, as they might in a typical smoker.

Selected accomplishments from the initial round of funding to the Yale TTURC include;

• Discovering that receptors for nicotine in the brain modulate brain circuits related to mood;
• Identifying molecular pathways in the brain that might be important for the transition from nicotine use to addiction;
• Determining that brain nicotine receptors are critical for the therapeutic action of antidepressants;
• Developing a new radiotracer that will not only be used to examine the effects of nicotine on the brain, but will also allow researchers to determine if nicotine acetylcholine receptor levels are altered in Alzheimer's disease, alcoholism, major depression and schizophrenia.
• Discovering that selegiline hydrochloride, a medicine used to treat Parkinson's disease, may help smokers quit;
• Establishing that low doses of the drug naltrexone reduced the amount of weight gain by those who were successful in quitting smoking;
• Determining that there is a market for new smoking cessation treatments, such as naltrexone, if they are more effective and if they can help people avoid weight gain while quitting;
• Analyzing factors associated with state level allocations to tobacco-control programs, and making associations between that funding and key variables of interest including public opinion, the state's smoking rate and whether the state is a major producer of tobacco;

In the next phase of studies the Yale TTURC will examine the following subjects;

• Animal Models to Understand Risk Factors for Treatment Resistance, Dr. Marina R. Picciotto, Ph.D., PI. This basic science project will use molecular/genetic and behavioral techniques to understand the interaction between nicotine use, alcohol drinking and appetitive behaviors, as well as sex differences in those areas.
• Modeling Smoking Relapse Behavior for Drug Development, Dr. Sherry McKee, Ph.D., PI. A novel laboratory method, designed to model the first occurrence of smoking during a cessation attempt will be used to examine how known precipitants of relapse – including nicotine deprivation, smoking availability and alcohol – facilitate a lapse. This method will be used for the purposes of medication screening.
• Targeted Interventions for Weight Concerned Smokers, Dr. Stephanie P. O'Malley, Ph.D., PI. Following up on initial findings, this study will determine whether low-dose naltrexone, which reduces weight gain, will help weight-concerned smokers be successful in quitting. Researchers also will explore how efforts to restrict eating while quitting smoking influence the ability to resist smoking, using the laboratory paradigm developed by Dr. McKee.
• Imaging Nicotinic and GABAergic Markers in Tobacco Smokers, Dr. Julie Staley, Ph.D., PI, Dr. Graeme Mason, Ph.D., co-PI. Using brain imaging techniques, men and women smokers will be compared to non-smokers to determine how smoking alters nicotine receptors and the major inhibiting neurotransmitter, GABA. An understanding of the regulatory effects of smoking and acute abstinence on these key neurochemical targets in the brain may lead to the identification of better pharmacotherapies for smoking cessation in men and women.

Here are some more detailed examples of work done by the Yale TTURC:

Yale studies examine nicotine's effect on brain

Scientists suspect that one of the keys to nicotine addiction lies within the brain at the receptors where nicotine first takes effect. These nicotinic acetylcholine receptors, the initial site of action in nicotine in the brain, will continue to be the focus of Dr. Julie Staley, Ph.D., and her group, in the Yale tobacco center's next phase of studies.

The Yale Transdisciplinary Tobacco Use Research Center (TTURC) was awarded more than $9 million to continue its studies through September 2009. Dr. Staley's project is one of four major projects funded by the renewal. There will be numerous smaller projects as well.

In the initial round of funding, Dr. Staley's group successfully evaluated a radiotracer (a drug tagged with radioactivity) that allows researchers to take pictures of where nicotine acts in the brain . Dr. Staley's group found that the radiotracer, ( S )-5-[ 123 I]iodo-3-(2-azetidinylmethoxy)pyridine of A-85380, also known as [ 123 I]5-I-A-85380, could be safely used in humans and they also determined the most reliable way to measure the drug in the human brain and approximately how long residual nicotine or active by-products remained in brain after the last cigarette.

Dr. Masahiro Fujita, Ph.D. of Yale was the lead author of the paper on the radiotracer ( Whole-body biodistribution, radiation absorbed dose, and brain SPET imaging with [ 123 I]5-I-A-85380 in healthy human subjects , European Journal of Nuclear Medicine Vol. 29, No. 2, February 2002). Dr. Edythe D. London , Ph.D., of the National Institute on Drug Abuse and the Departments of Psychiatry and Biobehavioral Sciences at UCLA, and Dr. Robert B. Innis , M . D . , Ph . D., of the Molecular Imaging Branch of the National Institutes of Mental Health, also played important roles in the development of the radiotracer , along with other researchers, Dr. Staley said.

“In our upcoming studies, we will evaluate what happens to the nicotine acetylcholine receptor in response to chronic smoking and whether this receptor is regulated differently between men and women,” said Dr. Staley, an assistant professor, and the Director of Psychiatry SPECT Imaging, in the Brain Imaging Division of the Department of Psychiatry at Yale. “And, because of the known effects of nicotine on mood and cognition, other studies are also using this radiotracer to determine if this receptor is altered in Alzheimer's disease, alcoholism, major depression and schizophrenia.”

Dr. Stephanie O'Malley, the principal investigator for the TTURC, said Dr. Staley's research fits well with the overall objectives of the center, which include investigating new treatments for smokers who find it hard to quit. The center will build upon and extend research findings from ongoing studies that suggest women, people worried about their weight, people who drink, and people who are depressed and/or anxious have a particularly hard time quitting.

“An understanding of the regulatory effects of smoking and acute abstinence on these key neurochemical targets in the brain may lead to the identification of better pharmacotherapies for smoking cessation in men and women,” said Dr. Stephanie O'Malley, a professor and director of the Substance Abuse Research Division in the Department of Psychiatry at Yale.

TTURC basic science project leads to clinical trial on treatment for depression

The co-morbidity of smoking and major depressive disorder coupled with the ability of many antidepressant subclasses to act as non-competitive nicotinic antagonists has led to the hypothesis that nicotinic antagonism may be critical for antidepressant efficacy.

Using co-treatment with subthreshold regimens of the nicotinic antagonist mecamylamine and the classical antidepressant amitriptyline, Dr. Marina Picciotto's laboratory has shown that the two treatments can have additive antidepressant effects in a rodent behavioral model of depression.

Further, this group showed that amitriptyline is an effective antidepressant in wild type, but not beta 2 nicotinic receptor knockout mice using both behavioral testing and assays of adult hippocampal neurogenesis.

These studies suggest that nicotinic receptors are an important molecular partner in antidepressant action. Dr. Tony George has translational evidence that this is the case in his clinical trial of mecamylamine as an adjunct therapy in treatment-resistant depressed patients on SSRIs.