by Angela Spivey, Neil Caudle, and Christine Thetford

John would get clean for a couple months. But as soon as his bills were paid, he'd start thinking about that house where he'd scored so many times. He could still see it — the peeling, dingy-white paint, the filthy brown carpet, the flower-print couch and mismatched kitchen chairs.

Maybe he'd be at a party. He couldn't find a girl. He'd start feeling out of place, so he'd get in his car and head to that house. "I'd drive by myself," he says. "I was doing something that nobody knew about, and I was getting away with it."

A guy stood lookout at the window. When he let John inside, John would feel a rush of relief. He didn't need a girl or a party. "Getting ready to do the drugs, the ritual, is just as important as the drugs itself," John says. "That's the high — the satisfaction of knowing that you're getting it."

Left: A guy stood lookout at the window. When he let John inside, there was a rush of relief. Photo by Jason Smith; click to enlarge.

John wasn't just imagining the feeling that came before he smoked crack. Carolina scientists say that the feeling may have a physical cause, a small burst of a brain chemical called dopamine, which is known for its role in pleasure. Regina Carelli and Mark Wightman have literally seen this dopamine release in the rats they study as models of human addiction.

Measuring Anticipation

Using a tiny probe with a very fast readout, Carelli and Wightman can measure what was once immeasurable — anticipation. Brain chemistry is a complicated business, employing billions of nerve cells called neurons. Carelli, associate professor of psychology, explains that neurons are like electronic circuits — constantly receiving, processing, and sending messages. In the brain, those messages are chemical signals called neurotransmitters. Dopamine is a neurotransmitter associated with pleasure.

For many years now, using a technique to measure electrical signals in rats' brains, Carelli and other researchers have seen that neurons are activated a few seconds before and after the rats pressed a lever to receive a dose of cocaine. Carelli considers self-administration (rather than injection) to be the most appropriate model of addiction, because the rats determine when they receive a dose of the drug.

But linking electrical signals with dopamine remained elusive. Until recently, the only tool available took readings slowly — every five minutes. Too slowly to detect all the signals the neurons were sending back and forth.

Ten Times Thinner than a Hair

Then, three years ago, Carelli enlisted the help of Wightman, professor of analytical chemistry. Wightman's research group had, two decades before, pioneered the use of ultramicroelectrodes — probes ten times thinner than a human hair — as sensors that could detect chemical messages in the brain. After perfecting this "fast-scan cyclic voltammetry" technique, they can now measure dopamine communications in brain cells ten times a second. The significance of this, Wightman says, is that they are now able to look at the conversations between neurons "on the timescale where these events are really happening."

Using this sensor, the researchers discovered that dopamine increases when trained rats first see the drug-dispensing lever — even before they press it. That anticipation of receiving the drug was enough to excite the rats and motivate them to press the lever. It's a chain reaction — the anticipation elicits a surge of dopamine, and the pleasure from the dopamine encourages them to follow through with taking the drug.

Right: When he'd smoke in the kitchen, he'd set up the toaster like a mirror, so he could see the front door reflected in it. Photo by Jason Smith; click to enlarge.

No method had ever been fast enough to correlate the behavior with that "preview" dopamine surge. Scientists had suspected it, but now Wightman and Carelli have conclusively demonstrated it. "What makes this research so novel," Carelli says, "is that no one had a way to detect dopamine's role in behavior on such a fast timescale before." The researchers published their findings in the April 10, 2003, issue of Nature.

The sensor that Wightman's research group developed also has the ability to detect other neurotransmitters, such as serotonin, norepinephrine, and histamine. But Wightman says they have chosen to restrict themselves to dopamine because it is more plentiful than the other neurotransmitters. "And it is the most relevant to drug addiction," Carelli says, since all types of addiction are believed to involve dopamine.

Left: Out of drugs and paranoid, he searched the hotel room for some protection. Then he crouched in the corner clutching a table knife — the only thing he could find. Photo by Jason Smith; click to enlarge.

The researchers presented the animals with a combination of drug-related environmental cues. An initial cue was the special chamber into which the rat was placed, but the researchers also played a tone and turned on a light every time the rats self-administered cocaine. When they introduced the same cues without offering cocaine, the sensor showed "the same rapid dopamine signaling, just like when they press the lever for the drug itself," Carelli says.

Just like John — to feel good, all he had to do was get inside that door.

To ensure that this dopamine surge was truly related to the drug-related environmental cues, the researchers also tested rats who had not been trained to self-administer cocaine. These rats showed no comparable increase in dopamine levels when presented with the lever and the light and sound cues. Carelli says, "This rapid dopamine signaling reflects a learned association between the stimuli and the drug."

The Road to Collaboration

You may wonder why a psychologist and a chemist are even working together — Wightman himself once did. The research his group had been doing five years ago (see Endeavors, Spring 1999, Mind Reader) was supported by the National Institute of Drug Abuse. This agency made Wightman an offer he couldn't refuse — if he wanted to continue to receive funding, he had to start working with a psychologist. They even had one in mind — Carelli.

At first, Wightman resisted. He was already leading a large research group and was leery of taking on more projects, especially with someone whose background was so different. But the funding agency was insistent. They organized a conference in Washington, D. C., and invited both Wightman and Carelli. Once the two scientists met and talked, Wightman realized the huge potential of their partnership.

Now he enjoys walking into his lab and seeing Carelli's students there, and she feels the same. They have collaborated on two additional grants, and many of their students are working together. They joke about it now, Carelli says, but "the truth is that we never could have done this project independently."

Wightman agrees. "On the one hand, Regina's laboratory understood the behavioral aspects involved in cocaine self-administration in rats," he says. "On the other hand, we had the analytical chemistry techniques to measure dopamine during these behaviors. This combined approach led to the new insights."

Wightman and Carelli are using the same tool to find out whether the anticipatory dopamine surge is specific to cocaine, or general enough to be triggered by the sweetener sucrose. If the dopamine surge is a general reaction, it may also occur in the presence of alcohol or cannabinoids (marijuana). Then there is the question of whether quinine, which the animals find bitter and aversive, would change the response.

Another direction, Wightman says, is to explore what dopamine is actually doing once it is released — how does it influence the electrical signaling of neurons? What effect does it have on the neuron that receives it? Wightman's team is developing a new technique to switch back and forth — detecting dopamine release from one neuron, then measuring electrical signals of another neuron that receives dopamine — so that they can map the activity of dopamine and how the neighboring neurons respond to dopamine's presence.

Wightman says, "It isn't even known, on a cellular level, what dopamine does to cells. One scientist said that for every fifty neuroscientists who study dopamine, there are fifty-one theories. But now we'll have the proper technology to investigate this."

Right: Sooner or later, John would head to that house. Getting ready to do the drugs, the ritual, was just as important as the drugs.

Sick at the Thought

If just the sight of a crack house or a drug-dispensing lever can trigger changes in the brain, can they also trigger changes in the immune system? Donald Lysle thinks so.

Several years ago, Lysle sat in a darkened room during a conference on addiction when the speaker projected a nineteenth-century image of a gaunt, hollow-eyed man smoking an opium pipe.

"This image of the sickly 'addict' has been commonplace for centuries," Lysle says. "But I wondered, why are they sick?"

In general, medical science and the public blame the lifestyles of drug users, who often have poor diets and risk injecting themselves with all kinds of pathogens each time they share needles under unsanitary conditions. Lysle, professor of psychology, suspected that the drugs themselves might somehow compromise the immune system, and his laboratory set out to test the idea. When the team gave opiates such as heroin and morphine to rodents, the effects were startling — a 90 percent reduction in immune response. The question was, how did drugs alter immune response so dramatically? To find out, Lysle and colleagues introduced drugs directly into a culture of living cells involved with immune response and found that there was no effect. It was only when drugs reached the central nervous system that immune responses changed.

To Lysle, this made perfect sense. His earlier work had shown that events stressful enough to alter the central nervous system also suppress immune responses. Since stress can impair health, it seemed likely that opiates would induce a similar effect by acting through the central nervous system. At the time, this was a controversial idea, mainly because scientists who studied the brain did not often collaborate with those who studied the immune system. "For the longest time neuroscientists and immunologists never actually talked to one another," Lysle says.

But at Carolina, they did begin to talk to one another, and a consensus grew that the immune system and the central nervous system were in fact communicating. For Lysle, the next question was how the brain processes information about the drug in ways that affect immunity. Could an environment associated with opioid drugs trigger a drug-like response that suppressed the immune system, even when drugs were not involved?

Earlier studies had shown that changing the environment drastically altered a drug user's physiology and behavior. Lysle remembered reading that Vietnam veterans who had used heroin during their tour of duty in the sweltering jungles of Southeast Asia came home to very different surroundings and did not continue using drugs. Laboratory research confirmed that environmental stimuli could control many of the physiological effects of a drug. So Lysle had plenty of reason to suspect that environment was a key factor, not only in drug addiction but in immune response as well.

To test this possibility, Lysle's team gave rats heroin in a compartment whose bedding, lighting, and sounds differed from those in the rats' home cages. After only two or three exposures to the drug, the rats learned to associate the new environment with heroin. In fact, when the rats were in the drug-related environment, their brain activity resembled the patterns of drug use, even when the drugs were absent. Further testing revealed that the environment associated with heroin also suppressed immune responses. "The effects were as pronounced as those from the drug itself," Lysle says.

At first glance, the message from all of this work seems very clear: drugs of abuse such as morphine, heroin, or cocaine are bad for your health. As a general rule, Lysle says, that's true, but the picture is growing more complex. Lysle's recent work with Kelly Carrigan and Roland Arnold of Carolina's Dental Research Center has found that drugs such as morphine can have a beneficial effect under conditions in which activating the immune system does more harm than good. Lysle believes that scientists may eventually develop therapeutics based on opiates such as morphine to rein in a hyperactive immune system without the addictive properties.

Meanwhile, addiction has become one of those magnetic topics that pull scientists out of their customary orbits and into the same high-energy field.

"The really interesting part of this work," Lysle says, "is that we have to reduce it right down to the molecular level, to find out what happens at the level of cells and receptors. But at the same time, we have to put the whole system back together and ask ourselves, what does it mean?"

Other Solutions

Finding the meaning in those small pieces could one day lead to more effective treatments for addiction. Wightman and Carelli, for instance, speculate that a drug could be developed that would block the surge of dopamine that comes just before drug use, short-circuiting the cycle of cravings.

Sometimes John would be out driving around and crave his crack pipe. So he'd drive through a car wash, where no one could see him. Photo by Jason Smith; click to enlarge.

In the meantime, people find other solutions. John, for instance, has been clean for four years. He says that he still recognizes some of his old triggers — the thought of that house, or driving through one of the fifteen states where he has used drugs. But those cues don't mean as much to him anymore. Now, the craving and his rejection of it happen almost at the same time. "I literally go through the roller-coaster ride of that thought in less than thirty seconds," he says.

To get to this point, though, he went through four rehab programs. What finally worked for him was group psychotherapy. At his final rehab, he says, a doctor and a group of other users helped him see that he was using drugs to hide from his past and his emotions. "I was out of money. My family wasn't speaking to me," he says. "That was the end of the road for me."

Graduate students in the labs of Carelli, Lysle, Dykstra, Picker, and Thiele work under a grant for training in research related to drug abuse from the National Institute on Drug Abuse.

Angela Spivey is associate editor of Endeavors magazine.

Neil Caudle is editor of Endeavors magazine.

Christine Thetford is a doctoral candidate in the department of chemistry at Carolina.