Investigations

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Brief exposure to low levels of nicotine, as little as that in a single cigarette, can cause lasting changes in the brain's 'reward' areas, report two University of Chicago Medical Center researchers in the October 2000 issue of the journal Neuron.

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," amplifying the drug's pleasing effects and boosting the desire to repeat the exposure.

By uncovering the precise cellular mechanisms of nicotine's effect, the study suggests new, more precise targets for drugs designed to block the powerful craving.

"This appears to be the crucial first step in the process of addiction," says neurobiologist Daniel McGehee, assistant professor in anesthesia and critical care and the study's director. "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 is estimated to cause 70 times more deaths in the United States than all other types of drug dependence combined.

"Nicotine addiction makes millions of people suck carcinogens into their lungs over and over again, day after day," says 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."

But drugs of abuse, like nicotine, can usurp the pathways, also stimulating the release of dopamine. McGehee and post-doctoral researcher Huibert Mansvelder, working with brain tissue from rats, demonstrated how nicotine takes control of the reward pathways. Nicotine alters neuron connections using a process similar to the cellular mechanisms underlying the creation of memory.

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. More excited, the neurons release more dopamine in the reward areas.

This cellular locus of addiction is farther "upstream" in the reward pathway than anticipated. McGehee and Mansvelder found 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, called the nicotinic acetylcholine receptor. There are many different nicotinic acetylcholine receptors, performing various roles throughout the body. But the good news is that the addictive process 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," adds McGehee, "can have a tremendous health impact."

- John Easton