A new study has provided the first molecular explanation for the "gateway sequence" of drug use. 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. Amir Levine, MD, Denise Kandel, PhD; Eric Kandel, MD, and colleagues at Columbia University Medical Centre found that nicotine causes specific changes in the brain that make it more vulnerable to cocaine addiction. Using a novel mouse model, they found that pre-reatment with nicotine greatly alters the response to cocaine in terms of addiction-related behaviour 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. 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.