Ahmed: Research, science bolster gateway drug theory

Claiming alcohol and nicotine are gateway drugs seems like a health-class scare tactic. Claiming alcohol and nicotine are gateway drugs seems like a health-class scare tactic. But a new Columbia University-led study lends credibility to this notion. No, your teacher wasn’t bluffing; you should consider this.

Lest you stop reading upon hearing the phrase “new study,” let me say first that one person leading the study, Eric Kandel, is a neuropsychiatrist who won the Nobel Prize in Physiology or Medicine in 2000 for his paradigmatic work on the neural basis of memory. He is also the author of “Principles of Neural Science,” the almanac for any serious neuroscientist. Amir Levine, a neuroscientist and psychiatrist also led the study.

The initial investigation began with an analysis by Kandel’s wife, Denise Kandel, published in “Science” in 1975. It detailed the alarming correlation between adolescent use of legal drugs and the subsequent use of illicit drugs. Drinking alcohol or smoking cigarettes, it said, is indicative of marijuana use, which in turn predicts use of drugs like cocaine and heroin.

The theory was controversial at the time, but now it has solid support. In today’s language, that means a chemical process has been identified. The new study, published in “Science Translational Medicine” this month, describes the mechanism responsible for the correlation between nicotine and cocaine use.

You might have heard of the brain’s reward center, an evolutionarily important survival mechanism. The area triggers rewarding sensations for life-sustaining behaviors like eating and drinking. This is the area commonly affected by drugs, which hijack the brain’s reward cycle for less-healthy behavior.

The area contains the nucleus accumbens (NAcc), which receives rewarding input from neurons in the ventral tegmental area (VTA), which secretes dopamine. Dopamine from the VTA reinforces behaviors, and the NAcc in turn sends inhibitory feedback to the VTA. This can be seen as a check to make sure the cycle doesn’t become exacerbated, leading to addiction.

Drugs like nicotine enhance dopamine release from the VTA to the NAcc, and inhibit the NAcc’s regulatory feedback to the VTA. This means the reward cycle can run into overdrive, and thus over time neurons can become acclimated to receiving large, effective doses of dopamine.

The authors of the study administered nicotine and cocaine to mice and analyzed their resulting behavior. They discovered that nicotine primes the reward center such that the response to cocaine is greater than that in a normal “non-smoker” mouse. Addiction was measured by the level of addiction-related behaviors exhibited after cocaine administration. Conversely, cocaine did not enhance mice’s response to nicotine.

The model is relevant to us because of shared brain morphology — both humans and mice have a reward center. In both mice and men, as well, the aforementioned enhancement only works if nicotine use precedes cocaine use. The epidemiology concurs. In adult humans, 90.4 percent of those between ages 18 and 34 have smoked cigarettes before using cocaine. Conversely, 2.4 percent of the same group uses cocaine first, according to the study.

Now for some molecular biology. The priming and enhancement of nicotine use is because of a number of cellular changes. DNA is usually wound up around spherical protein masses called histones. It is thus inaccessible for reading and protein production. Acetylation of the histones is a chemical process that frees up DNA for reading. Histone deacetylase is an enzyme that reverses this reaction, so DNA stays wound up. Nicotine acts by inhibiting this enzyme, and thus allowing the DNA of neurons in the reward center to become accessible.

The gene or part of DNA that nicotine opens for reading is the FosB gene, which helps create FosB protein. FosB protein is critical in cocaine’s ability to cause addiction. Administering nicotine before cocaine produces a level of this protein that amplifies cocaine’s effects. Consequently, cocaine can more readily enhance dopamine activity in the reward center, increasing the potential for addiction.

Alan Sved, a neuroscientist and department chair of Neuroscience at Pitt, had some words to share on the matter. “This work is related to research at Pitt by [our lab] that has shown that administering nicotine to rats markedly enhances the rewarding properties of other stimuli provided to the rats. An extension of this work would be that nicotine treatment would enhance the rewarding qualities of cocaine, which is what Levine and colleagues describe in their mice.” So nicotine, as an enhancer of many effects, is a chemical of particular importance.

One might ask why knowing the molecular underpinning of this phenomenon is important. The reasons are manifold. Before this work, for one thing, studies supporting the gateway drug theory could more readily be dismissed as statistical wand-waving. Now we have a real biological framework to support the theory, proteins and all.

Another reason is the implications it has for our current practices. Smokers trying to quit are prescribed a source of nicotine that does not harm their lungs — either dermal patches or chewing gum. However, if nicotine makes cocaine addiction more likely, is “safe” nicotine really the best answer for quitters? It might decrease the risk of lung cancer, but not cocaine addiction.

As this mechanism becomes better understood, it’ll come as no surprise if Big Pharma tries to capitalize on it. In fact, the researchers have already proposed a drug: a compound that could activate histone deacetylase enzyme to put the DNA out of commission, competing with nicotine’s effects. Would taking this compound in some form, perhaps through the same cigarette one is smoking, be the best idea? It diminishes nicotine’s gateway ability and also makes smoking safer if cocaine addiction is a worry.

Last week was Tobacco Awareness Week, during which participants urged the president to share compassionate words with those trying to quit. I didn’t think it could be done, but we now officially have another reason to discourage smoking. Although the study didn’t focus on alcohol’s effect, alcohol works its magic in the same brain center. We should probably stand by for another study.

When bodily mechanisms become common knowledge, many sectors will have a stake in it. The medical and pharmaceutical industries both stand to benefit. This knowledge then meets the public in the form of medical procedures and drug advertisements. However, it will always befit us to look at the original studies behind these therapies, as we can then begin to understand not just their benefits, but also their risks and larger implications.

Write Abdul at aba24@pitt.edu.