Brief exposure to low levels of nicotine, as little as that provided by a single cigarette, can cause lasting changes in the brain's "reward" areas, report two University of Chicago scientists in the August 2000 issue of the journal Neuron. The finding is a major advance in understanding the process of nicotine addiction.
The researchers discovered that nicotine uses a mechanism responsible for learning and memory to enhance the connections between one set of nerve cells that are sensitive to the drug and other nerve cells that register pleasure. They also demonstrate that the first exposure to nicotine can induce an enduring "memory trace," which amplifies the pleasing effects of the drug -- and boosts the desire to repeat the exposure.
By uncovering the precise cellular mechanisms of nicotine's effect, this study suggests new and more precise targets for drugs designed to block this powerful craving.
"This appears to be the crucial first step in the process of addiction," said neurobiologist Daniel McGehee, Ph.D., assistant professor in the department of anesthesia and critical care at the University of Chicago and director of the study. "Now that we know how this happens, we can begin to search for better ways to intervene."
The reinforcing effect of nicotine is the primary reason people cannot quit smoking, despite widespread awareness that smoking causes cancer, heart disease, stroke, emphysema, bronchitis, vascular disease, cataracts, impotence and many other health problems. Nicotine dependence has been estimated to cause 70 times more deaths in the United States than all other types of drug dependence combined. Nearly 25 million Americans alive today will die prematurely from smoking-related illnesses.
"Nicotine addiction makes millions of people suck carcinogens into their lungs over and over again, day after day," said McGehee. "If this knowledge leads to new ways of helping people quit successfully, it will be an important step for public health worldwide."
The brain reward areas serve to acknowledge and reinforce beneficial behaviors, for example eating when you're hungry. The system encourages the body to repeat pleasing behaviors by releasing dopamine, the neurotransmitter associated with the pleasant feelings, in the reward areas. "That was good," is the basic message of increased dopamine levels. "Do it again."
Unfortunately, drugs of abuse, such as nicotine, can usurp those pathways, providing the same sort of encouragement for some very harmful actions, such as smoking. They also do this by stimulating the release of dopamine.
McGehee and his colleague, post-doctoral researcher Huibert Mansvelder, PhD, working with brain tissue from rats, demonstrated how nicotine takes control of the reward pathways. Nicotine alters the connections between neurons using a process that is similar to the cellular mechanisms underlying the creation of memory. "In this way," Mansvelder said, "the brain erroneously learns that the intake of nicotine was good and remembers the sensations it caused."
The ability to remember things, such as pleasant sensations, is thought to depend on the strengthening of links between neurons. Nerve cells communicate with each other at synapses, junction points where chemical signals mediate communication back and forth. When a synapse is used a lot, there is a persistent strengthening of the communication. In effect, the more that one side of the synapse 'talks,' the better the other side 'listens,' and the more effective the communication becomes.
Nicotine appears to cause addiction by strengthening the excitatory connections on the neurons that make dopamine, which are found in the Ventral Tegmental Area (VTA) of the brain reward center. Thus, the neurons are more excited, which means that more dopamine is released within the reward areas.
This cellular locus of addiction is farther "upstream" in the reward pathway than anticipated. McGehee and Mansvelder demonstrate that nicotine's lasting effects result from the drug's interaction with a receptor on the synaptic endings, the part of the cell that sends the signals. When these endings are exposed to nicotine, there is a direct increase in the excitatory signal transmitted onto the dopamine neurons, which then increases dopamine release.
Nicotine stimulates neurons by attaching to a specific structure on the neuron, known as the nicotinic acetylcholine receptor. There are many different types of nicotinic acetylcholine receptors, performing various roles throughout the body. The addictive process fortunately appears to involve only one subtype, acetylcholine receptors containing the alpha7 subunit, making it a potential target for medications that could help smokers kick the habit.
"Anything we can do to discover even a slightly more effective method to help people stop smoking can have a tremendous health impact," added McGehee.
This study was funded by the National Institute of Neurological Disorders and Stroke, the Brain Research Foundation and the Netherlands Organization for Scientific Research.
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