Why Nicotine is a Gateway Drug

A new study in mice shows how tobacco products could act as gateway drugs, opening the door to use of illicit drugs. Nicotine, the researchers found, makes the brain more susceptible to cocaine addiction. The finding suggests that lowering smoking rates in young people might help reduce cocaine abuse.

Scientists have long recognized that cigarettes and alcohol raise the risk for later use of illicit drugs like marijuana and cocaine. In a recent national survey, over 90% of adult cocaine users between the ages of 18 and 34 had smoked cigarettes before they began using cocaine. Researchers suspected that nicotine exposure might increase vulnerability to cocaine. However, no one had identified a biological mechanism. A team of scientists, led by Dr. Eric Kandel at Columbia University and supported by NIH’s National Institute on Drug Abuse (NIDA), set out to investigate.

In Science Translational Medicine on November 2, 2011, the scientists reported that mice given nicotine in their drinking water for 7 days showed increased activity in response to cocaine. The animals also had changes in a brain signaling process called long-term potentiation.

Earlier research had shown that expression levels of a gene called FosB in the brain's striatum was linked to cocaine addiction. In the new study, investigators found that 7 days of nicotine administration caused a 61% increase in FosB expression. When given a dose of cocaine, these mice had an additional 74% increase in FosB expression compared to mice treated with cocaine alone. Reversing the order of the drugs didn't lead to a boost in FosBexpression.

Past studies found that cocaine modifies DNA structure through a process called histone acetylation. The changes affect FosB expression. The researchers tested whether nicotine increases FosB expression in the striatum by altering DNA in a similar way. They found that 7 days of nicotine treatment significantly increases histone acetylation. Nicotine does this, they discovered, by inhibiting molecules that reverse acetylation. By manipulating these molecules through other methods, the researchers showed that they could enhance or inhibit the effects of cocaine.

“Now that we have a mouse model of the actions of nicotine as a gateway drug, this will allow us to explore the molecular mechanisms by which alcohol and marijuana might act as gateway drugs,” Kandel says. “In particular, we would be interested in knowing if there is a single, common mechanism for all gateway drugs or if each drug utilizes a distinct mechanism.”

If nicotine works similarly in people, effective smoking cessation efforts might reduce the risk of addiction to cocaine and other illicit drugs.