By David N. Leff

Thanks to willing rats and human experience, neuroscientists long ago agreed that nicotine is an addictive drug. Tobacco companies are now conceding the point.

But there's much less concurrence, in laboratories and board rooms, on just how nicotine in the brain becomes so tenaciously habit-forming.

At Baylor College of Medicine, in Houston, neurophysiologist John Dani has been studying this many-faceted issue for the past three years. (See BioWorld Today, Oct. 24, 1996, p. 1)

In the November 1997 Nature, he offers an experimental answer to a relevant question: Why does the first cigarette of the morning seem so much more enjoyable than fags that follow throughout the day?

Dani's short answer constitutes the title of his article in Nature: "Nicotine activates and desensitizes midbrain dopamine neurons."

"What we wanted to do," he told BioWorld Today, "was try to find out what the cellular mechanisms might be for nicotine addiction, and for the compelling motivation to keep smoking.

"Nicotine," he pointed out, "does not exist naturally in the brain, but when it is obtained from tobacco, it can activate receptors on the midbrain dopaminergic neurons.

"In particular," he explained, "nicotine activates receptors on a small set of dopamine-releasing neurons in the ventral tegmental area at the center of the brain. But these cells project to very broad brain areas, such as the nucleus accumbens and prefrontal cortex. It's thought that the burst of dopamine released in these areas when nicotine first enters the body may be what helps a person experience the sensation of pleasure. How it does so," Dani added, "is still a very hot topic of study."

Much of that first cigarette's nicotinic high depends on anticipating the pleasure to come, as well as the actual bliss itself. Dani explained: "Wow! When I'm in bed, with my feet under the covers, I think to myself: 'When I wake up, the first thing I should do is grab a cigarette, because that's really going to have a happy impact on me, as if something really positive had just happened in my life.'"

At the neuronal signaling level, here's how Dani described this predictive euphoria and its fulfillment: "As we live our lives, we come to expect what the next moments are going to bring. Thus, a prehistoric hunter-gatherer might think: 'If I forage in a particular berry patch, if things go particularly well, then I'm going to be successful.'

"Then, if things go even better than expected, those behavior-reinforcing reward neurons may fire. What nicotine does," Dani went on, "is short-circuit all this lifetime stuff that causes the neurons to fire, as if the future were a lot better than you expect it to be. That, we found, would contribute to the sensation of pleasure."

The next thing he and his co-authors found was that "if the nicotine hangs in there for a long time, many minutes or hours, as is the case when someone smokes cigarettes, the neurons become numb, or desensitized. So the burst of firing that they first displayed goes away, and the neurons need to have the nicotine taken away before they can recover, and respond again to the drug. That is the situation during a nighttime of abstinence from tobacco."

"The upshot," he continued, "is that during a nighttime of sleep, for instance, when the smoker doesn't experience nicotine for eight hours or so, the brain cells can recover from this numbing, or desensitization, and the first cigarette of the day will cause the best firing of those neurons. It helps us to realize that first cigarette, whether you smoke it in the morning or at noon, may be the one that pushes people into nicotine addiction, as they seek the pleasure that may reinforce continued use."

He pointed out that "smokers are, in a sense, medicating themselves with nicotine during the day to feel more comfortable."

"This finding," Dani added, "may help us understand the dynamics of cigarette smoking in a way that will enable us to adjust the quitting medications, and how a smoker doses himself with them, to kick his cigarette habit.

"These dopamine neurons in the midbrain normally fire due to normal activities that help us conduct a good, successful life," he observed. "That means their activity has to come in from all sorts of sensory areas -- vision, taste, smell, hearing, touch. All this information from our environment is constantly converging on this small brain area, with its important neurotransmitter receptors.

"It turns out that nicotine, by short-circuiting all of this information, just activates those receptors in response to a cigarette. That," he commented, "really warps your system. A system that normally should have been responding to all sorts of sensory inputs from the environment, and processing them to lead a successful life, is now being commandeered by a little white tube that you can stick in your mouth."

Tracking Nicotine To Addictive Lair In Brain

In the experiments that Dani and his team reported, they collected ultra-thin slices of tissue from the ventral tegmental area of rat brains, and identified their neurons as dopamine-releasing. Into a bath of these tissue samples, they flowed low levels of nicotine, mimicking the concentrations seen by smokers' brains, and measured their electrophysiological activity.

In addition, they pipetted tiny squirts of various neurotransmitters alongside the cells, to mimic the brain's synaptic activity, and measured the effects of the nicotine on incoming electronic signals to those neurons.

"Probably the outcome of this work," Dani concluded, "is going to be bigger than just nicotine addiction. What it's helped us to realize, and people are converging on this idea anyway, is that in many, if not all, drugs of addiction, at least a part of their activity is via this system, and that in controlling it we may also help people take control, break their addiction, and stay off." *