Cigarettes and alcohol serve as gateway drugs, which people use before progressing to the use of marijuana and then to cocaine and other illicit substances; this progression is called the “gateway sequence” of drug use. An article in Science Translational Medicine by Amir Levine, MD, Denise Kandel, PhD; Eric Kandel, MD; and colleagues at Columbia University Medical Center provides the first molecular explanation for the gateway sequence. They show that nicotine causes specific changes in the brain that make it more vulnerable to cocaine addiction — a discovery made by using a novel mouse model.
Alternate orders of exposure to nicotine and cocaine were examined. The authors found that pretreatment with nicotine greatly alters the response to cocaine in terms of addiction-related behavior and synaptic plasticity (changes in synaptic strength) in the striatum, a brain region critical for addiction-related rewards. On a molecular level, nicotine also primes the response to cocaine by inhibiting the activity of an enzyme — histone deacetylase — in the striatum. This inhibition enhances cocaine’s ability to activate a gene called FosB gene, which promotes addiction.
The relationship between nicotine and cocaine was found to be unidirectional: nicotine dramatically enhances the response to cocaine, but there is no effect of cocaine on the response to nicotine. Nicotine’s ability to inhibit histone deacetylase thus provides a molecular mechanism for the gateway sequence of drug use.
Nicotine enhances the effects of cocaine only when it is administered for several days prior to cocaine treatment and is given concurrently with cocaine. These findings stimulated a new analysis of human epidemiological data, which shows that the majority of cocaine users start using cocaine only after they have begun to smoke and while they are still active smokers. People who begin using cocaine after they’ve started smoking have an increased risk of cocaine dependency, compared with people who use cocaine first and then take up smoking.
“These studies raise interesting questions that can now be explored further in animal models,” said study author Denise Kandel, a professor of Sociomedical Sciences at the Mailman School of Public Health. “Do alcohol and marijuana — the two other gateway drugs — prime the brain by the same mechanism as nicotine? Is there a single mechanism for all gateway sequences, or does each sequence utilize a distinct mechanism?”
The results also emphasize the need for developing effective public health prevention programs encompassing all nicotine products, especially those targeted toward young people. Effective interventions not only would prevent smoking and its negative health consequences but could also decrease the risk of progression to chronic use of illicit drugs.