"Memory" of Nicotine Lingers in the Brain, Say Scripps Research Scientists By Jason Socrates bardi Scientists at The Scripps Research Institute and Scripps Florida are reporting the results of one of the first studies looking at the long-term neurological effects of nicotine addiction on the brain's reward system. Their findings may have significant implications for people who are trying to quit smoking. Associate Professor Athina Markou, who is in the Scripps ResearchMolecular and Integrative Neurosciences Department at Scripps Research's La Jolla campus, and Paul Kenny, a former research associate in her laboratory, report in an upcoming issue of the journal Neuropsychopharmacology that nicotine has an unusual psychological property that may drive dependence. Nicotine induces a long-lasting activation of the brain's reward systems that is not seen after excessive consumption of other drugs of abuse, such as cocaine or heroin. This slight elevation in mood is there regardless of how much nicotine is consumed, and it persists long after the nicotine is gone from the body. "It's almost a memory of nicotine in the brain," says Kenny, who is now a staff scientist at Scripps Florida. "The reward system becomes hyperactive, even when the nicotine isn't there." This persistence of reward activity, Kenny adds, appears unique to nicotine among drugs of abuse and is probably crucial in maintaining the nicotine habit. Knowing this may have relevance to prevention of nicotine addiction and smoking cessation programs. Persistently Increased Reward Sensitivity Nicotine is one of thousands of chemical components of cigarette smoke, and it is the main ingredient in tobacco that leads to addiction, which fuels cigarette smoking, a major health problem in the United States. The latest report of the U.S. Surgeon General on the health effects of smoking calls it the leading preventable cause of death in American society. And according to the U.S. Centers for Disease Control and Prevention (CDC), one in five deaths in the United States is related to smoking, and more than 400,000 Americans die each year from it—through cancer, cardiovascular disease, and respiratory diseases. In the last few years, Markou and her colleagues at Scripps Research and at Novartis Pharma AG have been funded by a multi-year, $3.45 million grant from the National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA) to design new ways to treat depression and nicotine addiction. One of the goals of this grant is to look at the connection between cigarette smoking and depression, which could shed light on what makes nicotine so addictive, and how the same sorts of compounds used to treat depression might be used to treat nicotine addiction. Their interest in the connection between cigarette smoking and depression is what led Markou and Kenny to study the effect of nicotine on the brain's natural reward system. Although nicotine does not induce intoxication, Markou and Kenny expected the neurobiology of nicotine addiction to be similar to other addictive substances such as cocaine and heroin, in which these chemicals affects neurocircuitry in the reward centers of the brain and induce a measurable elevation in mood directly related to the presence of these drugs. This pleasurable action likely contributes to establishing the drug habit. Then, hours later when cocaine or heroin is no longer present, there is a diminished sensitivity to rewarding stimuli – the so-called 'crash' associated with drug withdrawal. In their study, Markou and Kenny looked at the effect of nicotine self-administration on brain reward systems in laboratory rodents. They allowed the rodents to have extended access to nicotine self-administration, and they directly measured the changes in neuronal activity in the brain. As predicted, the scientists found that nicotine acutely stimulates the brain's reward system and seems to enhance the normal pleasures in the environment for hours. Unexpectedly, however, rather than the depression-like state induced when cocaine and heroin leave the system, nicotine's elevation of mood persists. The measurements of neuronal activity in the brain's reward system one hour after the nicotine consumption looked similar to those twelve hours after consumption. In fact, this increased sensitivity to reward persists for days or weeks after the nicotine disappears. The excitation of these systems cannot be due to the presence in the brain of nicotine, which is readily metabolized by enzymes in the body so that all traces of it are gone after a matter of about three to four hours. So if the nicotine is metabolized and cannot be responsible for the elevation in mood, what is the explanation? One possibility is that nicotine leads to an upregulation of the brain receptors to which it binds—the nicotinic receptors. Since the neurotransmitter acetylcholine also binds to these receptors, the elevation in nicotinic receptors due to nicotine may be behind the persistent elevation in mood. Interestingly, a similar increase in activity of brain reward systems is seen in hungry rats. It is an interesting possibility that nicotine may be hitting the same reward pathways in the brain responsible for regulating the rewarding effects of food. "We're not exactly sure of the relevance of that," says Kenny, "but hopefully we can look at that in the future." The article, "Nicotine Self-Administration Acutely Activates Brain Reward Systems and Induces a Long-Lasting Increase in Reward Sensitivity" by Paul J Kenny and Athina Markou is available after September 28, 2005 as an advance online publication of the journal Neuropsychopharmacology. See: http://dx.doi.org/10.1038/sj.npp.1300905. This research was funded by the National Institutes of Health, the National Association for Research on Schizophrenia and Depression, and the Tobacco Related Disease Research Program of the State of California. More information: 1) The Health Consequences of Smoking, a report of the U.S. Surgeon General: http://www.cdc.gov/tobacco/sgr/sgr_2004/index.htm 2) Cigarette Smoking-Related Mortality, statistics compiled by the CDC: http://www.cdc.gov/tobacco/research_data/health_consequences/mortali.htm 3) Related Stories: "NIH Funds Scripps Research-Novartis Collaboration To Target New Treatments for Depression and Nicotine Addiction." See: http://www.scripps.edu/newsandviews/i_20031208/markou.html "The Down Side of Nicotine and Environmental Stimuli" See:

http://www.scripps.edu/newsandviews/i_20050718/markou.html

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Associate Professor Athina Markou's lab took a look at the long-term effects of nicotine addiction on the brain's reward system. The results were a surprise.

"It's almost a memory of nicotine in the brain," says Paul Kenny, a former research associate in the Markou lab who is now a staff scientist at Scripps Florida. "The reward system becomes hyperactive, even when the nicotine isn't there."