Published online 2 November 2011 | Nature | doi:10.1038/news.2011.627

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Molecular mechanism found for controversial 'gateway drug' hypothesis.

Smoking now may make you more susceptible to cocaine addiction later. Edyta Pawlowska/Glow Images

Nicotine causes changes in gene regulation that enhance the brain's subsequent response to cocaine. The finding, in mice, provides the first clear evidence for a molecular mechanism supporting the idea of 'gateway drugs'.

Epidemiologist Denise Kandel at Columbia University, New York, reported back in 1975 that drug-using adolescents had tended to start with cigarettes, which contain the addictive substance nicotine, and alcohol before progressing to more illicit substances such as cocaine1. The idea that smoking and alcohol act as a gateway, making teenagers more likely to experiment with other drugs, has proved controversial ever since.

Now Kandel has collaborated with her husband of 56 years, neurobiologist Eric Kandel, and other colleagues at Columbia, to probe the molecular biology underlying the gateway effect. In a study published today in Science Translational Medicine2, the team shows that, in mice at least, nicotine causes epigenetic changes — long-lasting changes in the control of gene expression — that subsequently boost the response to cocaine.

Hunt for a mechanism

Neurobiologists Eric Nestler and Alfred Robison of the Mount Sinai School of Medicine in New York suggested in a review published earlier this month that such gene priming is likely to be at work in drug addiction3. But their prediction was based on limited existing evidence. "This paper is exciting because it is one of the first well-defined characterizations of gene priming by a drug," says Robison.

“Adolescence is a time when the brain is very malleable.” Amir Levine

Columbia University

Amir Levine, a member of the Columbia team, acknowledges that there could be other reasons, such as social factors, for the progression from soft to hard drugs, but "adolescence is a time when the brain is very malleable", he points out. "We wondered if drug-induced brain alterations could have long-term molecular impacts."

To investigate, the researchers plied mice with nicotine, followed seven days later by cocaine. What they found was striking. Compared with mice on cocaine who had not previously received nicotine, the animals were 98% more active and 78% more likely to return to areas previously associated with the cocaine.

The reverse didn't hold, however. Cocaine had no effect on nicotine-induced behaviour.

The chromatin connection

To determine how nicotine boosts cocaine's impact, the researchers studied molecular markers of drug addiction, including the transcription of FosB, a gene implicated in addiction to many drugs of abuse, and the structural changes that regulate FosB expression.

"We found that nicotine works on the DNA-packaging system, known as chromatin," says Levine. Nicotine loosens chromatin, a complex material in which DNA is packaged up by histones and other proteins, by enhancing a process called histone acetylation, catalyzed by acetylase enzymes. Acetylation effectively opens up the packaging, enabling greater transcription of the FosB gene, he says. Nicotine does this by inhibiting another enzyme involved in gene regulation, histone deacetylase, which has the opposite effect on chromatin.

The authors backed up their results with additional experiments showing, for example, that the drug suberoylanilide hydroxamine acid, which inhibits deacetylases, simulates the effect of nicotine.

New life for an old hypothesis

The team also re-evaluated existing epidemiological data on the drug use of 1,160 high school students and found that it confirmed that smoking increased the risk of cocaine dependency in people – consistent with the findings in mice.

The research promises to reinvigorate the gateway-drug hypothesis, which Levine says has gained a bad reputation. "People think it's backed by conservative movements to make a case for making marijuana illegal, when it is simply the sequence of adolescent drug use as found in epidemiological studies," he says.

Frances Leslie, a neuropharmacologist at the University of California at Irvine, who was not involved in the study, says that part of the problem is that people don't want to believe that teenage smoking will sensitize them to other drugs. And because it's difficult to tease out social factors in human studies, animal work has an important role. Her own group has shown that nicotine is associated with 'risky' behaviour, including an increase in self-administration of cocaine, in adolescent rats4.

The molecular mechanism revealed by the Columbia team's work "is exciting because it may lead to therapeutic interventions", says Leslie. "Hopefully this paper will make it less controversial to use the term 'gateway drug' in future papers and grants," she adds.

The policy implications of the findings will undoubtedly be debated. Laura Bierut, a psychiatrist at Washington University in St Louis, Missouri, who focuses on the genetic epidemiology of addiction, says the Columbia study suggests that existing policies aimed at cutting smoking may be having a larger effect on public health than thought.

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It should also help to guide epidemiological studies to tease apart the relationship between cocaine use and smoking, she says, including the effects of the age that someone starts smoking, how much they smoke, and what other drugs they take.

Levine and Eric Kandel now hope to determine whether alcohol and marijuana similarly prime the response to illicit drugs or have a different effect. "Is there a common gateway mechanism or a family of gateway mechanisms?" says Kandel.