by Angela Spivey

Drugs are easy. To feel good, you don't have to earn a good grade or get asked out on a date. You just ingest, say, a line of cocaine, and in less than five minutes you feel a rush of pleasure like no other.

But Linda Dykstra will tell you that inside your brain drugs are complicated. She and other scientists know only a few facts for certain about what happens to cause that rush. They're finding out more every day, but sometimes the new facts only confound what they know.

The mice in Dykstra's lab, for example, like cocaine. Or as Dykstra would say, they find it reinforcing. Any psychology textbook will tell you that, for normal mice, this is no big deal. But Dykstra's mice are different. They've been genetically altered in a way that disrupts the systems that manage two brain chemicals — the neurotransmitters dopamine and norepinephrine.

Dopamine is famous for its role in pleasure. At one time, it was even called the "pleasure chemical." So it'd be natural to think that cocaine — basically powdered pleasure — would work by using the dopamine system.

Today, Dykstra points out, the "pleasure chemical" nickname "has lost favor as research in this area has progressed." Scientists do know that cocaine works by blocking the dopamine transporter (a mechanism that regulates the chemical), thereby increasing levels of dopamine in the brain.

But they also know that, while dopamine plays a prominent role in cocaine's effects, it doesn't work alone. "Clearly, dopamine levels are increased when animals self-administer cocaine," says Dykstra, professor of psychology. But other brain chemicals are involved, and possibly other brain systems in addition to the classic, dopamine-based reward system.

If dopamine were the only chemical involved in cocaine's effects, Dykstra's mice wouldn't develop a preference for it. Their genetic alteration — deletion of the dopamine transporter — keeps dopamine always available in the synapses between their brain cells. So if cocaine worked solely by prolonging dopamine circulation, then these mice probably wouldn't be affected by it. They already have plenty of dopamine available.

Dykstra and Marc Caron, professor of cell biology at Duke University, have found that, even with the transporters for dopamine and norepinephrine deleted, these mice still show some affinity for cocaine. That may be because another neurotransmitter, serotonin, is involved.

"In the last year, a good deal of evidence has come out that serotonin may also play a very important role in cocaine's reinforcing effects," Dykstra says. Researchers at the National Institute on Drug Abuse, for example, have bred and tested mice that have transporters for both dopamine and serotonin deleted. These mice do not find cocaine reinforcing. Other studies indicate that a separate suite of neurotransmitters and receptors — the NMDA system — is important in the effects of cocaine and somehow changes the actions of those more famous neurotransmitters — dopamine, serotonin, and norepinephrine.

model mice

Until a couple years ago, Dykstra hadn't worked much with mice. But she had plenty of experience measuring reinforcement in other animals such as rats and primates. So Caron asked her to take a look at his genetically altered mice. Caron says, "I was excited to have Linda in the lab because it gave us a different perspective. Our lab is mostly a biochemistry and molecular biology lab, and her expertise is mostly in behavior." Dykstra spent the better part of a year and a half in Caron's lab, designing experiments to test preference for cocaine and learning the particulars of working with mice.

Today, in her own lab, Dykstra is meticulous with the mice that Caron has bred for her. When she gives an injection of either cocaine or saline, she doesn't talk much. She does the job quickly and gets out. She wants to ensure that these excitable mice don't accidentally start to associate cocaine with, say, a loud voice. She wants them to associate it only with the cues that she designs, such as a particular experimental chamber.

Mice, like humans, tend to want to return to the places where they've gotten high. Scientists call that tendency "conditioned place preference." After Dykstra injects a mouse with cocaine, she puts him into a white chamber with a mesh floor. Technician Scott Robertson changes the litter material in the pan underneath the chamber. He puts in corn-cob bedding, then he tears open an orange package. It is, yes, a tea bag.

"Bigelow Orange Pekoe," Dykstra says. Whenever this mouse receives cocaine, he's put into the white chamber. The tea bag in that chamber's litter pan makes it smell distinctive, so the mouse can tell the difference between it and the black chamber, which is where he's put on the days when he receives only an injection of saline.

After six days of alternating cocaine with saline, the researchers open the door that seals off the passageway between the two chambers. A mouse is put in, and he can roam freely between the two. If the mouse chooses to stay mostly in the compartment that he associates with cocaine, then, as Dykstra says, he has developed conditioned place preference. "The hypothesis is that if the cocaine is reinforcing, the mice will spend more time on the side of the chamber that we paired with cocaine," Dykstra says. "Which they do."

a long haul

These are mice, after all, and while the findings reveal a lot, they alone won't provide a solution to addiction. Dykstra and her colleagues hope that their basic research, combined with work from clinical scientists, will eventually lead to new pharmaceuticals or other treatments to help beat addiction.

But Dykstra knows from experience that it will be a long haul. Starting in the 1980s, Dykstra and a dozen graduate students spent about ten years exploring the effects in animals of a drug called buprenorphine. They started out looking at the drug's pain-relieving abilities, then they studied its effect on appetite, and then they explored whether, after repeated doses, taking away the drug would produce withdrawal. This work, along with that of many other scientists — including those at the National Institute on Drug Abuse, Johns Hopkins University, and drug company Reckitt Benckiser — led to the United States' October 2002 approval of buprenorphine for treatment of heroin and morphine dependence.

Buprenorphine provides an alternative to methadone, which is used to wean addicts off of heroin or morphine. Buprenorphine is milder than heroin and methadone and does not cause as intense a withdrawal, so it may be easier to get patients completely off of it, Dykstra says. And, private physicians, not just traditional drug-treatment programs, can prescribe it.

Maybe, after another ten or twenty years and thousands of experiments, science can create another buprenorphine story — a pharmaceutical to help users short-circuit some of their cravings. If that happens, Dykstra will be part of it.

In collaboration with Allyn Howlett, professor of biology at North Carolina Central University, Dykstra will study how stress affects the action of morphine and other drugs. That work is part of a $7.5 million grant to N.C. Central to expand research on chronic medical conditions affecting members of minority groups.

Angela Spivey is associate editor of Endeavors magazine.