The Unyielding Power of Dopamine

Question: What makes dopamine such a powerful chemical?

Nora Volkow: Dopamine is a chemical substance that serves to send messages between two cells in the brain, and that's, we call neurotransmitters. There are many neurotransmitters and dopamine plays a key role in the areas of the brain that enable a wide variety of functions, best known is movement and when your dopamine cells die, for example, you cannot initiate movement, and that's Parkinson's disease.

But the effects of dopamine go way beyond movement and one of actions, very relevant for drug abuse and addiction, is it modulates the areas of the brain involved with our ability to perceive reward reinforcement and to be motivated by that reward to do actions. So, for example, it's so important that if you can generate through trans-genetic, genetic technologies, you can generate in a mouse that does produce synthesized dopamine. These animals will die of starvation because they don't have the motivation to engage in the behaviors to go and eat the food. You can rescue this animal by injecting dopamine into the areas of the brain that control this. But if you don't to that, these animals will die of starvation. And that really epitomizes how extraordinary important dopamine is. It gives you that energy, that drive to do things.

Now, drugs of abuse, we know that for the past 50 years, all of them, whether it's legal or illegal, they don't make any distinctions over there in terms of the pharmacology, they increase dopamine in specific areas of the brain, of the limbic brain. And this ability to increase dopamine when a person takes a drug is associated directly with what we call rewarding or reinforcing effects. So if you can actually manipulate it in such a way that to interfere with the ability of a drug to increase dopamine, than that drug is no longer pleasurable.

And so that's why dopamine is so important. Understanding why certain drugs can produce addiction and others not. If a drug produces increases in dopamine in these limbic areas of the brain, then your brain is going to understand that signal as something that is very reinforcing. And will learn it very rapidly, and so that the next time you get exposed to that stimuli, your brain already has learned that that's reinforcing and you immediately what we call a type of memory that's conditioning, will desire that particular drug.

Now, these mechanisms are not developed in our brains to take drugs. These mechanisms of dopamine signal reinforcement and once you have experienced it, getting conditioned to it is extraordinary important way for nature to ensure that humans, as well as animals, will perform behaviors that are indispensable for survival. So therefore, it shouldn't surprise us that behaviors such as eating or sexual behavior are linked with increases in dopamine and in the same areas that drugs do it. There are differences though, because natural reinforcers increase dopamine as a function very much of the context. What do I mean by that? If you're hungry, for example, and you get exposed to food, that will increase dopamine much more than if you just finished eating. And so as you eat, the ability of food to increase dopamine goes down and eventually disappears. And because it disappears, you are no longer motivated to eat the food.

Question: How is dopamine related to drug addiction?

Nora Volkow: What happens with drugs though, on the other hand, is they do not decline the ability to increase dopamine. So a person may take a hit of cocaine, snort it, it increases dopamine, takes a second, it increases dopamine, third, fourth, fifth, sixth. So there's never that decrease that ultimately leads to the satiety. And this is believed that then these differences between the normal responses of the dopamine stimuli as it was developed through evolution to serve physiological functions, versus the ways that drugs do it, much more potently, longer duration of action. And it does not decline with repeated administration. It's believed to trigger the adaptations, the plastic changes in our brain, that eventually will lead, in those individuals that are vulnerable, to addiction. To the process of addiction, which is a condition whereupon the person, with repeated administration of drugs, no longer can control his or her ability to decide when they take or they don't take the drug. This is fundamentally a stage where that individual has lost control and has intense drive to compulsively take the drug.

And that's what we call addiction. Not everybody that takes drugs, actually, becomes addicted. We've come to recognize, for example, that approximately 50% of the vulnerability of a person to take, to become addicted is genetically determined. So that vulnerability has a very strong genetic component. It also has other processes that determine vulnerabilities. For example, if you get exposed to drugs when you're very young, very early adolescence, you're much more likely to become addicted than if you get exposed to the same drugs when you're an adult. And this has to do with the fact that the adolescent brain is much more neuroplastic than the adult brain. And as a result of that, a drug, which triggers this adaptation process, is likely to produce these changes faster in an adolescent and it's also the duration of those changes is likely to be much longer lasting in an adolescent than it is an adult. So these are two processes as it relates to addiction.

Recorded on November 6, 2009

Drug addiction researcher Nora Volkow walks us through the singular chemical that drives substance abuse.

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Sponsored by Charles Koch Foundation
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The surprise reason sleep-deprivation kills lies in the gut

New research establishes an unexpected connection.

Image source: Vaccaro et al, 2020/Harvard Medical School
Surprising Science
  • A study provides further confirmation that a prolonged lack of sleep can result in early mortality.
  • Surprisingly, the direct cause seems to be a buildup of Reactive Oxygen Species in the gut produced by sleeplessness.
  • When the buildup is neutralized, a normal lifespan is restored.

We don't have to tell you what it feels like when you don't get enough sleep. A night or two of that can be miserable; long-term sleeplessness is out-and-out debilitating. Though we know from personal experience that we need sleep — our cognitive, metabolic, cardiovascular, and immune functioning depend on it — a lack of it does more than just make you feel like you want to die. It can actually kill you, according to study of rats published in 1989. But why?

A new study answers that question, and in an unexpected way. It appears that the sleeplessness/death connection has nothing to do with the brain or nervous system as many have assumed — it happens in your gut. Equally amazing, the study's authors were able to reverse the ill effects with antioxidants.

The study, from researchers at Harvard Medical School (HMS), is published in the journal Cell.

An unexpected culprit

The new research examines the mechanisms at play in sleep-deprived fruit flies and in mice — long-term sleep-deprivation experiments with humans are considered ethically iffy.

What the scientists found is that death from sleep deprivation is always preceded by a buildup of Reactive Oxygen Species (ROS) in the gut. These are not, as their name implies, living organisms. ROS are reactive molecules that are part of the immune system's response to invading microbes, and recent research suggests they're paradoxically key players in normal cell signal transduction and cell cycling as well. However, having an excess of ROS leads to oxidative stress, which is linked to "macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging." To prevent this, cellular defenses typically maintain a balance between ROS production and removal.

"We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation," says senior study author Dragana Rogulja, admitting, "We were surprised to find it was the gut that plays a key role in causing death." The accumulation occurred in both sleep-deprived fruit flies and mice.

"Even more surprising," Rogulja recalls, "we found that premature death could be prevented. Each morning, we would all gather around to look at the flies, with disbelief to be honest. What we saw is that every time we could neutralize ROS in the gut, we could rescue the flies." Fruit flies given any of 11 antioxidant compounds — including melatonin, lipoic acid and NAD — that neutralize ROS buildups remained active and lived a normal length of time in spite of sleep deprivation. (The researchers note that these antioxidants did not extend the lifespans of non-sleep deprived control subjects.)

fly with thought bubble that says "What? I'm awake!"

Image source: Tomasz Klejdysz/Shutterstock/Big Think

The experiments

The study's tests were managed by co-first authors Alexandra Vaccaro and Yosef Kaplan Dor, both research fellows at HMS.

You may wonder how you compel a fruit fly to sleep, or for that matter, how you keep one awake. The researchers ascertained that fruit flies doze off in response to being shaken, and thus were the control subjects induced to snooze in their individual, warmed tubes. Each subject occupied its own 29 °C (84F) tube.

For their sleepless cohort, fruit flies were genetically manipulated to express a heat-sensitive protein in specific neurons. These neurons are known to suppress sleep, and did so — the fruit flies' activity levels, or lack thereof, were tracked using infrared beams.

Starting at Day 10 of sleep deprivation, fruit flies began dying, with all of them dead by Day 20. Control flies lived up to 40 days.

The scientists sought out markers that would indicate cell damage in their sleepless subjects. They saw no difference in brain tissue and elsewhere between the well-rested and sleep-deprived fruit flies, with the exception of one fruit fly.

However, in the guts of sleep-deprived fruit flies was a massive accumulation of ROS, which peaked around Day 10. Says Vaccaro, "We found that sleep-deprived flies were dying at the same pace, every time, and when we looked at markers of cell damage and death, the one tissue that really stood out was the gut." She adds, "I remember when we did the first experiment, you could immediately tell under the microscope that there was a striking difference. That almost never happens in lab research."

The experiments were repeated with mice who were gently kept awake for five days. Again, ROS built up over time in their small and large intestines but nowhere else.

As noted above, the administering of antioxidants alleviated the effect of the ROS buildup. In addition, flies that were modified to overproduce gut antioxidant enzymes were found to be immune to the damaging effects of sleep deprivation.

The research leaves some important questions unanswered. Says Kaplan Dor, "We still don't know why sleep loss causes ROS accumulation in the gut, and why this is lethal." He hypothesizes, "Sleep deprivation could directly affect the gut, but the trigger may also originate in the brain. Similarly, death could be due to damage in the gut or because high levels of ROS have systemic effects, or some combination of these."

The HMS researchers are now investigating the chemical pathways by which sleep-deprivation triggers the ROS buildup, and the means by which the ROS wreak cell havoc.

"We need to understand the biology of how sleep deprivation damages the body so that we can find ways to prevent this harm," says Rogulja.

Referring to the value of this study to humans, she notes,"So many of us are chronically sleep deprived. Even if we know staying up late every night is bad, we still do it. We believe we've identified a central issue that, when eliminated, allows for survival without sleep, at least in fruit flies."

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