Ask a Caltech Expert: Henry Lester on Nicotine Addiction and the Brain

Tobacco originated in the Americas, where humans have known some of its effects for at least 10,000 years. Beginning some 500 years ago, ocean crossings spread tobacco use to all other continents. We are essentially the only species that has learned how to use small amounts of plant toxins—which provide the selective advantage of sickening or poisoning animals who might eat them—for our own purposes. For tobacco, that toxin is nicotine. In addition to their historical medicinal and ritual uses, these substances, over time, have come to serve as guides, models, and touchstones for learning about the brain and opening many fields of neuroscience.

We have learned from tobacco and nicotine that it is possible to isolate single chemicals from plants that cause toxic effects on herbivores and valued effects on people. We've learned that it's possible to define chemical processes in the human brain that are activated, inhibited, or otherwise manipulated by those substances.

Why do people smoke?

The effects of nicotine, and the reasons people continue to smoke, depend on the fact that the drug acts on a group of receptors in various regions of the brain. Some receptors for the natural neurotransmitter acetylcholine are also highly sensitive to nicotine, so we call them nicotinic receptors. They are present in the part of the brain that makes dopamine, for example, and when nicotine acts on the dopamine cells, people experience a sense of well-being. There are also nicotinic receptors in the amygdala, and those may very well play a role in the fact that people get relief from stressful stimuli when they smoke. There are other places in the brain where nicotine acts, mostly in the forebrain, so some people smoke because they believe smoking helps them think better. Nicotinic receptors in other parts of the brain control appetite, so some people also smoke as a way to control their weight.

What happens in the brain when people smoke?

When nicotine enters the lungs, it's in the brain 20 seconds later. In this journey, nicotine has traveled through the cells in the lungs to the blood—and then from the blood to the brain, passing through the blood-brain barrier. In all, nicotine passes through six membranes when it's smoked or vaped.

Once nicotine is in the brain, it activates the most sensitive nicotinic receptors on membranes of nerve cells, or neurons, but it also travels through the membrane to enter the neuron. Finally, it passes into the organelles of the neuron, where proteins, including the nicotinic receptor, are being made. When a person smokes, nicotine actually helps the cell to assemble more nicotinic receptors, which travel out of the endoplasmic reticulum (part of the cellular transportation system) and onto the surface of the cell. It's as though nicotine is acting as a pharmacological "chaperone" to bring those receptors to the surface of the cell.

We have labeled this process "inside out" pharmacology. In trying to unravel the cell biology of nicotine addiction, my lab and others study how this so-called chaperoning or upregulating of nicotinic receptors is necessary for the early stages of nicotine dependence, ultimately underlying the brain's addiction to nicotine. When a person stops taking nicotine, the natural acetylcholine cannot sufficiently activate the upregulated receptors. They produce craving and other symptoms of withdrawal.

How can neuroscience lead to treatments for nicotine addiction?

Around a billion people still smoke, so we clearly have more to learn about effective treatments for nicotine addiction. Medications that can help include bupropion, a classical antidepressant, which mostly helps people who are depressed to stop smoking; and varenicline, which imitates nicotine in some ways but prevents nicotinic receptors from being fully activated.

Some nicotine cessation products, such as gums and patches and inhalers, use nicotine itself in the hope that it can be delivered in small enough quantities and over a long enough period of time that nicotine receptors will only be partially chaperoned, helping to reduce upregulation while the individual works on quitting smoking.

Vapes approved for safety by the US Food and Drug Administration (FDA) are considered reduced-risk nicotine products because they do not expose people to tobacco smoke, which is so much more harmful than the single addictive component—nicotine. But a major issue is that if a person does not switch completely from smoking to vaping but rather still takes one or two cigarettes a day—so-called dual use—this is enough to trigger some tobacco-related diseases, in particular negative cardiovascular effects. One danger of vaping is that it can potentially introduce someone to nicotine who then will become a dual user.

Mesh nebulizers are part of a remarkable new set of emerging products that deliver nicotine by turning it into an inhalable mist—similar to how an asthma medication works. These nebulizers, while they contain nicotine, are considered a new form of candidate nicotine replacement therapy rather than a reduced-risk nicotine product. If they work, they will be approved as medications by the FDA. The reduced-risk products like vapes will still be around, but the nebulizer will be prescription only and will deliver nicotine so rapidly that it may be more effective for some people for smoking cessation. Scientists will need to know which people will be helped and how long they should use the new nicotine replacement therapies.

We still need more and better science to figure out the pharmacokinetics of nicotine: How fast does it enter the body? How long does it stay in the body? To that end, along with a team of collaborators—including Caltech professors Wei Gao (professor of medical engineering), Dennis Dougherty (George Grant Hoag Professor of Chemistry), and Stephen Mayo (Bren Professor of Biology and Chemistry), and Professor Neal Benowitz of UC San Francisco—we have been working to develop a wearable device that resembles the continuous glucose monitor used by Type 1 diabetes patients.

We will use this monitor to measure nicotine while a person smokes or vapes or uses a nicotine pouch so that we can fully understand how an individual metabolizes nicotine and relate this knowledge to a century's worth of work on nicotinic receptors and nicotine addiction.

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