Nicotine primes brain for cocaine use: Molecular basis of 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.

Columbia University's Mailman School of Public Health Founded in 1922 as one of the first three public health academies in the nation, Columbia University's Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health. Its over 300 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change & health, and public health preparedness. It is a leader in public health education with over 1,000 graduate students from more than 40 nations pursuing a variety of master's and doctoral degree programs. The Mailman School is also home to numerous world-renowned research centers including the International Center for AIDS Care and Treatment Programs (ICAP), the National Center for Disaster Preparedness, and the Center for Infection and Immunity.

Columbia University Department of Psychiatry & NYS Psychiatric Institute Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the nation and has contributed greatly to the understanding and treatment of psychiatric disorders. Located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Medical Center campus in Washington Heights, the department enjoys a rich and productive collaborative relationship with physicians in various disciplines at Columbia University's College of Physician's and Surgeons. Columbia Psychiatry is home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders, eating disorders, and childhood psychiatric disorders. The 2000 Nobel Laureate Eric Kandel was recognized for research that helped elucidate the cellular processes that underlie learning and memory – contributions that have implications for treating conditions such as Alzheimer's and age-related memory loss. Columbia Psychiatry's solid scientific footing earned its scientists a landmark grant to support its stem cell research program in 2008. Visit http://columbiapsychiatry.org/ for more information.

Columbia University's Mailman School of Public Health Founded in 1922 as one of the first three public health academies in the nation, Columbia University's Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health. Its over 300 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change & health, and public health preparedness. It is a leader in public health education with over 1,000 graduate students from more than 40 nations pursuing a variety of master's and doctoral degree programs. The Mailman School is also home to numerous world-renowned research centers including the International Center for AIDS Care and Treatment Programs (ICAP), the National Center for Disaster Preparedness, and the Center for Infection and Immunity.