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The Quest for Pharmacotherapies to Treat Tobacco Use Disorder

More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder


Tobacco use is a persistent public health issue. It kills up to half its users and is the cause of nearly 90% of all lung cancers. The main psychoactive component of tobacco is nicotine, primarily responsible for its abuse-related effects. Accordingly, most pharmacotherapies for smoking cessation target nicotinic acetylcholine receptors (nAChRs), nicotine’s major site of action in the brain. The goal of the current review is twofold: first, to provide a brief overview of the most commonly used behavioral procedures for evaluating smoking cessation pharmacotherapies and an introduction to pharmacokinetic and pharmacodynamic properties of nicotine important for consideration in the development of new pharmacotherapies; and second, to discuss current and potential future pharmacological interventions aimed at decreasing tobacco use. Attention will focus on the potential for allosteric modulators of nAChRs to offer an improvement over currently approved pharmacotherapies. Additionally, given increasing public concern for the potential health consequences of using electronic nicotine delivery systems, which allow users to inhale aerosolized solutions as an alternative to smoking tobacco, an effort will be made throughout this review to address the implications of this relatively new form of nicotine delivery, specifically as it relates to smoking cessation.

Significance Statement Despite decades of research that have vastly improved our understanding of nicotine and its effects on the body, only a handful of pharmacotherapies have been successfully developed for use in smoking cessation. Thus, investigation of alternative pharmacological strategies for treating tobacco use disorder remains active; allosteric modulators of nicotinic acetylcholine receptors represent one class of compounds currently under development for this purpose.

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Advancing Our Understanding of Tobacco Use in Vulnerable Populations

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Response to Britton et al.

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A rational approach to e-cigarettes – challenging ERS policy on tobacco harm reduction

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Trying just one cigarette leads to a daily habit in majority of people, study suggests

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Why Your Brain Craves Cigarettes When You Drink

You’re experiencing the weird effect nicotine has on memory.

You know the feeling. You’re two, maybe three drinks in, and you suddenly get a special hunger. It’s like a void that you hadn’t noticed, and now you want to fill it with something hot. Something so hot and filthy that you’ll regret it when it’s over, but oh God I spend my whole life not doing things I’ll regret, just give me this one goddam thing. Please.

And the strangest part of all this is that you don’t smoke. Or rarely. In fact, you can go weeks without smoking. But then you mix in some alcohol, and all your nicotine circuits come online.

So what’s going on? Why is your brain doing this?

According to Dr. John Dani, a neuroscientist and expert on the mechanisms of addiction from the University of Pennsylvania, the urge to smoke is two-pronged. The first part results from the way nicotine affects memory, but the other is in how nicotine combines with alcohol to reduce dopamine levels. Together the two mechanisms make cigarettes seem delicious.

Let’s break that down a little more. Firstly, with the effects on memory.

In 2009, Dr. Dani’s team published a study examining how nicotine supercharges the formation of memory pathways. What they did was run laboratory mice through two compartments in a pen. In one compartment, the mice received a dose of harmless saline, while in the other they received a dose of nicotine. Unsurprisingly the mice quickly learned to spend more time in the nicotine compartment. But what’s really interesting is the affect the nicotine had on their brains.

“Compared to injections of saline, nicotine strengthened neuronal connections, sometimes up to 200 percent,” explained Dr. Dani. “And this strengthening of connections underlies new memory formation. We found that nicotine could strengthen neuronal synaptic connections only when the so-called reward centers sent a dopamine signal. And that was the critical process in creating the memory associations.”

So on the one hand, the study just underlined something we already knew: Feel-good activities make us want to do them again. But on the other, it showed on a neurological level how our memories of smoking cigarettes get hardwired into the brain. And more important, how all these associated memories—such as drinking and hanging with friends—all get bundled into these same, nicotine-reinforced memory pathways.

“I remember recently finishing an experiment with a colleague, and we went to a bar,” explained Dr. Dani. “I had known him for many years and never knew he smoked, but then he admitted he could really go for a cigarette. He said he hadn’t smoked in 20 years, not since high school. But now he has a few drinks and feels the urge to smoke.”

So that’s one reason you want a cigarette with your beer, but there’s another. And again it involves Dr. Dani’s rodent experiments.

It’s been known for a long time that, taken separately, alcohol and nicotine bolster dopamine in the brain. Because of this, Dr. Dani and his team theorized that if nicotine and alcohol were consumed together levels of dopamine would rise even higher. But it turned out the opposite was true. While rats that had been dosed with nicotine were shown to consume more alcohol, their dopamine levels actually flatlined.

Surprised, Dr. Dani and his team repeated the entire experiment. But they got the same results. After a lot of head-scratching, they realized the combination of nicotine and alcohol was actually initiating a release of stress hormones that stopped the release of dopamine. Or in more simple terms: Drinks and cigarettes will make you happy if consumed separately. But together, they’ll make you less happy.

So the reason people keep smoking and drinking is to regain that happiness. Theoretically, it’s a cycle that starts when alcohol dredges up those positive memories of smoking. But then smoking a cigarette, after drinking, drops your levels of dopamine. So there’s again an urge to drink more to recuperate levels of happiness-inducing dopamine, and the cycle starts over.

According to Dr. Dani, this hypothesis is consistent with other observations around smoking and drinking. As he says, “I was inspired by some work from Norway that showed one of the biggest predictors if someone is going to be picked up drink-driving is whether or not they smoked when they were young.”

But none of this answers the biggest question of all—will having a cigarette with your beer kill you? As always the answer comes in some pretty uncertain probability stats. So instead Dr. Dani gave us some more facts about social smokers.

“What you’re describing is called a ‘chipper’—somebody who doesn’t smoke very often but will under certain circumstances,” he says. “And what I’d recommend is that you just don’t. Because it’s really, really common for that habit to slide into regular use. And then it’ll be really hard to give up.”