Nicotine on the Brain

Marina Picciotto, a neuroscientist and professor of psychiatry, as well as deputy director of the Kavli Institute for Neuroscience at Yale University, explores links between the molecular level in the form of individual receptors, and their effect on cells, brain circuits, and behavior.

“One person who vapes likened their first try of nicotine vaping that comes in a candy flavor to crack cocaine wrapped inside a marshmallow,” she says.

Humans do experiments on their nicotinic receptors whenever they take in nicotine, “so there are implications for smoking cessation and also for disorders related to reasons people smoke,” says Picciotto. She also hopes it will one day be feasible to target the system for anxiety, depression, and appetite control.

To get there, her lab is trying to “sort of pull molecular interactions at the cell and the dynamics of receptor activation through all the levels of complexity of how the brain works to discover their role in shaping our interaction with the environment,” explains Picciotto.

In the past, a big gap was the timescale at which neurotransmitters activating receptors were released. “The receptors we’re interested in are for the neurotransmitter acetylcholine, which are also the receptors for nicotine,” she adds. “There are always links between what these receptors do within circuits and what you do to yourself each time you take in nicotine,” she says.

Her lab has used genetically encoded sensors to measure how acetylcholine release affects the brain’s networks—in real time—while animals do complex behaviors like learning how to associate a reward (including a milkshake!) with things within the environment or how to avoid a bigger, scary mouse.

For many years, the way acetylcholine works within muscle was thought to be how it works within the brain as well. Turns out, this is wrong.

“We found nicotinic receptors on almost every kind of neuron within the brain,” says Picciotto. “They’re not clustered across from the site where acetylcholine is released like within a muscle; instead, they’re diffusely localized on different compartments of a neuron.”

This discovery ushered in a new way of thinking about how acetylcholine works within the brain: as a neuromodulator that changes the state of the brain and its entire network.

Picciotto now wants to answer these questions: What does it mean to change the state of the brain via a modulator? And if we have nicotinic acetylcholine receptors on both excitatory and inhibitory neurons within the same part of the brain, and both are exposed to the release of acetylcholine, what is it doing to these receptors to change the network?

She suspects in some cases it’s changing the basal activity of a whole set of neurons. “For example, in a scary situation, stress increases the firing rate and release of acetylcholine,” Picciotto explains. “We also know that the ability of neurons within the amygdala—one of the fear-sensing parts of our brain—to be activated by these anxiety-provoking environments is dependent upon acetylcholine signaling.”

In mice models, her lab can increase or decrease the input of acetylcholine to areas of the brain they know process fearful or anxiety-provoking stimuli to explore its impact on the network’s overall activity.

The amygdala, for example, is important for learning about associations between predicting danger within the environment and then the outcome. Acetylcholine signaling through these nicotinic receptors is important for both the baseline activity of the structure and for plasticity—the activity and connection between neurons within that structure changes after a learning event.

“If we block nicotinic receptors, we decrease the overall excitability of the whole network within the basal amygdala,” Picciotto says. “It’s acting at different levels to not only change the excitability but also the connectivity between neurons within that structure, so later on the same stimulus will have a different effect on the structure.”

The brain evolved to help us interact with our environment in a homeostatic manner. “As conditions change, we want to be in tune with our environment,” she points out.

Since acetylcholine can tune networks by activating both excitatory and inhibitory neurons within the same network, the end result of activating nicotinic receptors is that it drives activity to its mean (average) state. If you have a very active network, adding the neuromodulating effect of acetylcholine decreases its activity and drives it back to the mean.

But if a network is very quiet, the overall effect of activating this neuromodulator will increase activity within the network.

“We need to be able to change systems homeostatically under normal conditions,” Picciotto says. “We get into trouble when activity is prolonged, whether via a pharmacological agent, let’s say nicotine, or a blocker of the breakdown of acetylcholine, or perhaps through genetic mutations, because this homeostatic effect disappears.”

When this happens, it may “disrupt the balance between excitation and inhibition and lead to anxiety disorders, with too much activity of the stress-related parts of the brain,” she adds. “In contrast, in neurodegenerative diseases like Alzheimer’s, the cholinergic system is lost. Those neurons die and cognitive decline, dementia, occurs. So the system evolved to become really good at tuning between whatever is happening within your environment and inside your brain. Too much or too little can result in dysfunction. We need our acetylcholine systems to work just right.”

Targeting the acetylcholine system for anxiety, depression, and weight control may finally be on the horizon. “It’s tough to do pharmacologically because it’s a system where these receptors are almost ubiquitous, so it’s difficult to figure out how to make a homeostatic drug,” Picciotto says. “But I’m convinced we will find the right way, hopefully within my lifetime, to target this system for anxiety or depression, and similarly for disorders of metabolism like obesity.”

There’s clear coordination of the effect of acetylcholine receptors within the periphery around metabolism that “are coordinated with the effect of acetylcholine centrally within the brain on appetite,” she says. “So here’s a system where you have the possibility to use the same neurotransmitter and at least some of the same receptors to coordinate the brain and body response to the environment—which is something we’re very interested in exploring.”