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Nicotine is addictive because it activates the brain’s dopamine network, which makes us feel good. UC Berkeley researchers now show in experiments with mice that high-dose nicotine also activates a recently discovered dopamine network that responds to unpleasant stimuli. This aversive dopamine network could be harnessed to create a therapy that increases the negative effects and decreases the rewards of nicotine. (Image credit: Christine Liu, UC Berkeley)
If you remember your first hit of a cigarette, you know how sickening nicotine can be. However, for many people, the benefits of nicotine outweigh the negative effects of high doses.
Researchers at the University of California, Berkeley have now mapped part of the brain network responsible for the negative consequences of nicotine, opening the door to interventions that could increase aversive effects to help people quit smoking.
While most addictive drugs at high doses can cause physiological symptoms leading to unconsciousness or even death, nicotine is unique in making people physically ill when inhaled or ingested in large quantities. amounts As a result, nicotine overdoses are rare, although the advent of e-cigarettes has made “nic sickness” symptoms such as nausea and vomiting, dizziness, rapid heartbeat and headaches more common.
The new research, conducted in mice, suggests that this aversive network could be manipulated to treat nicotine addiction.
“Decades of research have focused on understanding how nicotine reward leads to drug addiction and what the underlying brain circuits are. In contrast, the brain circuits that mediate the aversive effects of nicotine are largely understudied,” said Stephan Lammel, associate professor of molecular and cell biology at UC Berkeley. “What we found is that the brain circuits that are activated after a high aversive dose are actually different from those that are activated when nicotine is delivered at low doses. Now that we have an understanding of the different brain circuits, we think perhaps we can develop a drug so that when nicotine is taken at low doses, these brain circuits can be co-activated to induce an acute aversive effect. This could be a very effective treatment for nicotine addiction in the future, which currently does not we have”.
Lammel and Christine Liu, who recently earned her Ph.D. of UC Berkeley, also found that nicotine receptors in the reward pathway are desensitized by high doses of nicotine, which likely contributes to the negative experience of high doses.
“Inhibitory inputs and desensitization of nicotine receptors on the same dopamine neurons contribute to decreased dopamine signaling in the reward pathway, and then to decreased feelings of pleasure and thus to behavioral aversion,” Liu said.
Lammel, Liu, graduate student Amanda Tose and their colleagues described the brain circuits involved in nicotine aversion in a paper accepted by the journal Neuron and now published online.
The yin and yang of dopamine
Nicotine, like cocaine and heroin, is known to cause addiction by activating the body’s reward network: nicotine binds to receptors on cells that release the neurotransmitter dopamine in the brain, where it affects everything from pain perception and mood to memory. The dopamine network generally provides positive feedback that reinforces our desire to seek out pleasurable activities.
Christine Liu and Yichen Zhu in Stephan Lammel’s lab at UC Berkeley. Liu, now a postdoctoral fellow, was one of the leaders of the nicotine research. Zhu attended as an undergraduate researcher. (Photo courtesy of Christine Liu, UC Berkeley)
But three years ago, Lammel and his colleagues discovered a parallel dopamine network that responds to unpleasant stimuli by releasing dopamine in different areas of the brain than the dopamine reward network. The discovery of this yin-yang nature of dopamine came at a time when it became clear that dopamine performs quite different functions in various areas of the brain, exemplified by its role in voluntary movement, which is seen affected in Parkinson’s disease.
Lammel’s team has since found that some chemicals also stimulate the negative dopamine network. Lammel, Liu and Tose looked closely at nicotine’s effects on the body precisely because of its known aversive effects at high doses, and found that it also activates the network.
“This subcircuit we reported had a major impact on the field,” Lammel said. “For the first time, we identified this particular subcircuit of the dopamine system that was activated by negative emotional stimuli, such as a burst of electric shock. Now, we have discovered that an entirely different stimulus, a pharmacological stimulus, a drug, activates the same system. This means that the system is specially designed to be activated by aversive stimuli.”
To demonstrate this for nicotine, Liu and his colleagues infused mice with the drug and measured second-by-second dopamine release in the brain using a newly developed technique called dLight-based fiber photometry. Previously, dopamine could only be measured over periods of minutes, obscuring the neurons’ short-term responses to dopamine.
They then used chemical antagonists to inactivate a specific nicotine receptor called alpha-7 in the aversion network, which reduced the effects of aversive nicotine on neuronal activity. Subsequent optogenetic experiments eliminated the aversive behavior.
“In animals where we were able to silence this population of neurons, we actually saw a strong preference for high-dose nicotine,” Liu said. “So by silencing the circuit, we were able to show with certainty that this was a very important neural encoder of the behavioral aspect of high-dose nicotine.”
The only drug designed to help with nicotine cessation, varenicline, might work by increasing aversion via the alpha-7 receptor and decreasing desensitization at the alpha-4/beta-2 receptor, he said, but that’s currently unknown. its precise mechanism of action.
Lammel noted that drugs that block the alpha-7 nicotinic acetylcholine receptor might not work as a treatment for tobacco or nicotine addiction because they would block many necessary functions of the receptor. But identifying this nicotine receptor as key to mammals’ aversion to high-dose nicotine will help researchers develop targeted drugs to adjust the body’s response to a typical dose a smoker would ingest when lighting a cigarette.
“Maybe in the future it will be an approach for nicotine addiction therapy, where we use gene editing technologies to selectively target these receptors in specific brain circuits and then overexpress or eliminate receptors,” said Lammel. “What we provide here is a blueprint of a brain circuit and nicotine receptor subtype that is critically important for the aversive properties of nicotine.”
This work was supported by the National Institutes of Health (1R01DA042889), the California Tobacco-Related Disease Research Program (26IP-0035), the One Mind Foundation (047483), the Foundation for Research in brain (BRFSG-2015-7) and Wayne and Gladys Valley Foundation. Liu, now a postdoctoral fellow at UC San Francisco, was a Gilliam Fellow at the Howard Hughes Medical Institute and an NSF Graduate Research Fellowship Program (GRFP) Fellow. Tose was an NSF GRFP fellow.
Other co-authors of the paper are Jeroen Verharen, Yichen Zhu, Lilly Tang, Johannes de Jong and Jessica Du of UC Berkeley and Kevin Beier of UC Irvine. All Berkeley researchers are members of the Helen Wills Neuroscience Institute on campus.
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