CHICAGO--Smoking a single cigarette may provide enough nicotine to initiate the addictive process, a recent study found. That is because small amounts of nicotine, roughly equivalent to what is found in one cigarette, can produce long-lasting changes in the dopaminergic reward centers of the midbrain. By studying rat brain tissue, University of Chicago researchers found that the nicotine in cigarettes not only directly stimulates nicotinic acetylcholine receptors in the ventral tegmental area (VTA), one of the dopaminergic reward centers of the midbrain, but also alters synaptic function in the VTA.[1]

"This is a mechanism whereby nicotine enhances dopamine output by increasing the excitatory drive to the dopaminergic neurons," explained Daniel S. McGehee, PhD, an Assistant Professor in the Department of Anesthesia and Critical Care at the University of Chicago. Increased dopamine release in the brain is thought to contribute to addiction and is an effect of all addictive substances, he noted in an interview with PULMONARY REVIEWS.

In the study by Huibert Mansvelder, PhD, and Dr. McGehee, the direct stimulatory effect on the nicotinic acetylcholine receptors in the midbrain was short-lived because these receptors desensitized in a matter of seconds. However, nicotine also induced a long-term potentiation of excitatory input to the dopamine neurons.

This phenomenon, said Dr. McGehee, probably explains the sustained rise in dopamine release that follows nicotine exposure; the root cause appears to be activation of presynaptic alpha7 subunit--containing nicotinic acetylcholine receptors on glutamatergic terminals. This activation results in an ongoing increase in the excitatory input to the VTA.

A NICOTINE BATH

To produce their findings, the researchers studied nicotinic modulation of excitatory synaptic transmission onto VTA dopamine neurons in brain tissue slices, which were placed in a recording chamber and perfused with artificial cerebrospinal fluid (CSF) bath. The tissue samples contained intact portions of the brain reward center, including glutamatergic terminals.

"Then, we did patch-clamp recordings, which are basically microelectrode recordings of the electrical activity of the dopamine neurons," explained Dr. McGehee. To assess the effect of brief nicotine exposure on this activity, the researchers added nicotine to the artificial CSF bath and observed changes in synaptic transmission after the brain tissue had been exposed for about two minutes.

WHAT IS THE SIGNIFICANCE?

The study's findings provide greater insight into why cigarettes are so addictive. Nicotine's ability to induce long-term potentiation of the excitatory input to brain reward centers appears to be a vital early step in the addiction process, particularly when taken in the context of previous research correlating increased brain dopamine levels with reinforcement of addictive behavior.[2]

"Hopefully, we can someday use this information to develop new treatments to help people quit smoking," said Dr. McGehee. Since the long-term potentiation of dopamine release is caused by nicotine's activation of alpha7 subunit--containing nicotinic acetylcholine receptors, future smoking cessation research may focus on finding a ligand that can inactivate those receptors. The result could be a marked reduction in nicotine's addictive effect, Dr. McGehee speculated.

--Timothy Begany

References
1. Mansvelder HD, McGehee DS. Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron. 2000;27:349-357.
2. Stolerman IP, Mirza NR, Shoaib M. Nicotine psychopharmacology: addiction, cognition and neuroadaptation. Med Res Rev. 1995;15:47-72.

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