Oct. 18 2011

Columbia scientists Eric and Denise Kandel have been married since 1956, but it took 50 years, a Nobel prize and two phone calls before they started their first scientific partnership – an effort to unravel the molecular basis behind the gateway hypothesis of drug use. The two presented their latest findings to a packed Alumni Auditorium during the Mailman School of Public Health’s Grand Rounds Series, “A Life-Course Approach to Prevention.”

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Denise and Eric Kandel in 1956 (photo courtesy of Denise and Eric Kandel)

University Professor and Nobel Prize winner Eric Kandel, MD, told the story of his first scientific collaboration with wife Denise Kandel, PhD, professor of sociomedical sciences, this way: One summer in the mid-90s, while the Kandels were vacationing on Cape Cod, Eric got a phone call from an NIH program director. The caller had good news: Eric’s grant application would be funded, but he also a bold prediction: “By the way, we think you’re going to win a Nobel Prize.”

“Oh I hope not so soon,” said his wife, when Eric recounted the phone call. “All the studies show, once you win a Nobel, you no longer have new ideas.”

In 2000, Denise Kandel answered the call from Stockholm that carried the news of Eric’s Nobel for his research in learning and memory, and “since then, the challenge has been, how to convince Denise that I’m still intellectually worthy of our partnership,” Eric Kandel said during the lecture.

Luckily for Eric Kandel, an opportunity arose, and the rest of the tag-team lecture by the Kandels recounted how the two have developed a new approach to provide new answers to the question: Why does the use of legal drugs precede the use of illegal drugs?

Since the 1970s, Denise Kandel has studied the use of legal and illegal drugs: who uses drugs, what drugs do they use, and when do they start using. Her groundbreaking work uncovered a remarkably common trajectory: teenagers who use marijuana almost always use cigarettes or alcohol first. And adolescents who go on to harder drugs almost always use marijuana before trying cocaine or heroine. The sequence from alcohol and cigarettes to cocaine is one of the most consistent findings in drug abuse research, seen in every Western country regardless of legal constraints or social attitudes toward drug use.

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Denise Kandel's research shows that the use of illegal drugs (e.g. cocaine) is always preceded by alcohol or cigarette use. New studies with her husband Eric suggest cigarette smoking primes the brain for addiction to other drugs.

The association is real, but why does the use of legal drugs always precede the use of illegal drugs? That question was hard to answer with epidemiological methods, Denise Kandel said, so in a 2003 JAMA editorial she proposed using animal models to determine if use of one drug physically changes the brain, increasing the risk of using a second drug. “I began looking for a collaborator,” Denise Kandel said. Conveniently, the one she found shared her commute from home to Columbia University Medical Center.

“At the time, I thought we were in a position to look seriously at the molecular and cellular mechanisms that might underlie the gateway trajectory,” Eric Kandel said. “We had learned enough about short-term and long-term memory, and others had learned that the same processes involved in memory are also involved in addiction.”

Processes in the mouse brain involved in long-term memory, he has since found, are greatly altered when cocaine use occurs during or shortly after chronic nicotine exposure. The effects on memory are not seen when either drug is used alone, nor when nicotine exposure occurs after cocaine use.

“This gives us an insight into the molecular basis of the gateway hypothesis,” Eric Kandel said. “We think that nicotine produces the perfect environment for cocaine to activate genes that turn on a long-term memory of the illegal drug. One of the reasons cocaine is so addicting is that most people are smokers when they try it.”

“What surprised us about the research was that it came up with new questions about drug use that we had never asked before,” Denise Kandel said. “The mice findings suggest people are most likely to get addicted to cocaine if they’re active cigarette smokers. Now we’re trying to see if we can test this idea in human populations using epidemiological methods.”

The new findings and hypotheses generated by the collaboration between the Kandels “to my mind demonstrates the extraordinary power and extraordinary necessity of interdisciplinary science,” said DeLamar Professor Linda Fried, MD, MPH, dean of the Mailman School of Public Health.

Article courtesy of Columbia University College of Physicians & Surgeons.