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Smoking could lead to cocaine use

Add it to the list of smoking’s ills: Researchers at the Medical School have found new evidence that smoking cigarettes may encourage cocaine use.

The researchers, led by Nobel laureate Eric Kandel and research scientist Amir Levine, found that nicotine increases signs of cocaine addiction in mice. In a study published in Science Translational Medicine earlier this month, they suggested that decreasing smoking might lead to a reduction in cocaine use.

Doctors have long had evidence that drug use proceeds in a recognizable sequence, with most people using hard drugs like cocaine only after using alcohol, tobacco, and then marijuana. The so-called gateway hypothesis holds that soft drug use increases the odds of hard drug use, but critics have pointed to a lack of evidence that one causes the other.

This study might provide that evidence. Herbert Kleber, the director of the medical school’s Division on Substance Abuse, said the new findings are the first biological explanation for the gateway hypothesis, at least in the case of nicotine and cocaine.

“The key point of the Levine and Kandel findings is that we are seeing the possible smoking gun,” said Kleber, who was not involved with the study. “We don’t have to simply rely on epidemiologic data, we can come up with a plausible biologic mechanism.”

The researchers treated mice with nicotine and then cocaine. According to Kandel, a neuroscience professor, behavioral markers of cocaine addiction nearly doubled in mice pretreated with nicotine, compared to mice who received only cocaine. The pretreated mice also showed more evidence of addiction-related changes in their brains’ synaptic connections.

“The pretreatment with nicotine tremendously increases the response to cocaine,” Kandel told Spectator.

Most significantly, the researchers found that this response was caused by increased expression of an addiction-related gene known as FosB. Nicotine, they discovered, inhibits the enzymes that counteract the expression of FosB—in other words, it promotes FosB’s expression.

This newly identified molecular mechanism raises the possibility of new treatments for addiction. The researchers treated the mice with a drug known to discourage acetylation—the process that leads to FosB’s expression—and found that it almost entirely reversed the normal effects of cocaine.

“[It] actually creates the opposite of nicotine basically … you don’t see that increase in FosB,” Levine said. “It’s virtually blocked.”

The researchers also found that nicotine only increased signs of cocaine addiction if the two were administered to mice simultaneously—a two-week gap between nicotine and cocaine caused the effect to disappear, suggesting that nicotine’s influence is at least partly reversible.

In addition, the study included a new analysis of data from human populations, showing that most cocaine users were smoking at the time they started using cocaine, and that people who began using cocaine while smoking were subsequently more likely to become dependent on cocaine.

Kandel said that the gateway hypothesis and the new findings do not mean “that every smoker is going to go on cocaine.”

“The smoking population is gigantic and the amount of people that go on to cocaine is small,” Kandel said. “But insofar as people go on to cocaine they are very likely to come from the smoking population.”


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