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The Hacking of the American Mind The Science Behind the Corporate Takeover of Our Bodies and Brains Chapter 3. Desire and Dopamine, Pleasure and Opioids
Author: Robert H. Lustig Publisher: New York, NY: Penguin Random House. Publish Date: 2017 Review Date: Status:📚
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All of these boil down to the same thing: reward. Regardless of the species, the motivation to attain reward (eat, fight, mate) remains virtually intact and unchanged throughout evolution. It makes sense that reward is a pretty strong and unflagging driver of emotion. There are myriad rewards out there, many shaped by culture, religion, and/or reality TV. However, the underlying, unflagging, and omnipresent truth is the drive to attain it. The impetus to get out of bed is generally a quest for reward, whether it’s going to work in order to pay the electric bill, or entering the fiery gates of Mordor to destroy the One Ring. For me, it’s two cups of coffee. Virtually every human endeavor is imbued with an inherent reward. Reward has been the predominant driving force since Homo sapiens inhabited the planet. In fact, reward has been a primary driver of personal and collective behaviors since our vertebrate forebears emigrated from the primordial ooze. If we didn’t like sex and food, we would never eat anything or reproduce. Reward is how humans (and other species) get things done; it is literally survival of the species.
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Manifestations of reward are evident in all measures of personal triumph (that of business titans and/or presidents). Your salary is a general measure of your competence—that is, the reward you provide to others, and that same salary is your reward as well. And manifestations of reward remain the indices of successful companies (quarterly report) and societies (gross domestic product). Our society does not hurt from the inability to access reward. We’ve made it our highest priority. Now it’s everywhere and ripe for the taking, and virtually nobody needs any extra strategies other the ones they already possess to locate and access it: you need go no further than social media, online porn, your drugstore, your liquor store, or your refrigerator. Reward is first and foremost. Reward is the end. And sometimes reward literally becomes your end. Because one reward is never enough.
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When reward becomes the primary goal, overwhelming all else, the end consequence can be addiction—perhaps the nadir of unhappiness. Therefore, understanding the inner workings of reward is paramount to any discussion of personal or societal benefit or detriment.
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The reward pathway is where some of our most basic survival instincts, such as eating and mating, are housed and expressed. The pathway and its mechanisms are thought to have evolved to ensure perpetuation of the species: if there weren’t some level of enjoyment to procreation, genes would never get passed on. Despite the varied substances and behaviors that drive reward, the neural pathways and signaling mechanisms are surprisingly similar for all of them. Up until recently, the reward pathway was thought to be a one-way express lane to pleasure. But new studies have revealed that the experience of reward is actually two intertwined and conjoined pathways and experiences, with two sets of neurochemicals and two sets of receptors. Although science can piece the two apart, we humans tend to experience them either simultaneously or in quick and rapid succession. The two phenomena can be summed up as: (1) motivation or desire, mediated by the neurotransmitter dopamine and its receptors. Dopamine is responsible for the outward manifestations of “seeking” behaviors. This is then followed by: (2) consummation or pleasure, mediated by a class of neuromodulators called endogenous opioid peptides (EOPs, specifically beta-endorphin, enkephalin, and dynorphin) and their receptors, collectively known as opioid receptors. These pleasurable sensations that EOPs generate in the consummation of reward are all experienced inwardly. Thus, on the outside looking in, it’s the dopamine effect you see.
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While there are several other brain peptides and neurotransmitters involved in facilitating the reward response, for ease of explanation, we can distill the discussion down to the trigger of the pathway: dopamine. Understanding dopamine will be enough to explain how and when we jump the rails. To wit, virtually all pleasurable activities (sex, drugs, alcohol, food, gambling, shopping, the internet) employ the dopamine pathway in the brain to generate the motivation. But too much dopamine starts the downward spiral toward misery. If you can put “-aholic” on the end of the word (alcoholic, shopaholic, sexaholic, chocaholic), then the dopamine pathway is in play. Dopamine is the fulcrum on which reward tips your scale, or trips your trigger, or floats your boat. The motivation pathway is a conduit between two deep brain structures, the ventral tegmental area (VTA) and the nucleus accumbens (NA) (see Chapter 2).
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It’s a signal from one brain center to another. The cell bodies (the main part of neurons, also known as perikarya) that drive the impulses we experience as motivation are located in the VTA, part of the primitive brain over which you have no control. The VTA serves many purposes, primary among them being dopamine production. These cell bodies then send the dopamine signals to the nerve endings of a second set of neurons that reside in the NA, as well as some others. When we talk about dopamine and reward, we’re talking about the communication between the VTA and NA neurons. The VTA makes the dopamine and sends it across the synapse to the dendrites of the NA. There are other neurotransmitters and hormones involved in modifying the dopamine signal, but we can limit our discussion of motivation to just dopamine without losing anything in translation.
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Dopamine is a Jekyll-Hyde neurotransmitter. Without it, you’re a laconic couch potato; too much and you can get aggressive and paranoid. In other words, like so many things in science and medicine, there is a sweet spot, an optimal level within the dynamic range of experience where the system functions at its best. This can best be illustrated with a bell-shaped curve, which one can travel along backward and forward, depending on your physiologic and emotional state (Fig. 3-1). If you’re at the low end (on the left) of the bell-shaped curve, you have little motivation for reward. A slight upswing to the right of a dopamine boost can help you liven up your mood and experience excitement. But if you’re already at the top of your bell-shaped curve, and you get that same dopamine boost, it can result in a new transitional state that can be quite unpleasant. Moreover, your current position on that bell-shaped curve can be changed by your experiences with the many forces, including stresses and medicines, that you are exposed to every day.
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Fig. 3-1: Ring my bell—the curve of reward. The reward pathway functions optimally in the middle of its dose-response curve. Less reward yields lethargy, while more reward yields irritability.
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Anti-psychotics (e.g., risperidone), by blocking dopamine action, shift the curve to the left, while dopamine transporter blockers (e.g., cocaine) shift the curve to the right. Also, genetic polymorphisms alter your place on the curve. The Val158Val genotype of the dopamine receptor shifts the curve to the left, while the Met158Met genotype shifts the curve to the right. Obese people are right shifted, so more food, meaning more dopamine, confers less reward. (1) Obesity. Obesity plays havoc with your dopamine system in very consistent ways. If you’re obese, you’re already past that central optimum, on the right side of the dopamine curve. Stress will push you even further to the right (see Chapter 4). Then throw in a food cue (an advertisement for Oreos) and the dopamine in your head becomes so blaring, you have nowhere to go but down.1
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The hormone leptin (which comes from your fat cells and tells your brain you’ve had enough Häagen-Dasz) normally reduces dopamine firing in the reward center (VTA)2 and moves you leftward on the curve (I want ice cream—I ate ice cream—yay, ice cream!).3 But when your neurons are leptin resistant,4 as seen in chronic obesity, leptin doesn’t work; it can’t extinguish that dopamine signal, dopamine action stays high, and you’re on to your second, third, and fourth pint—hoping for an ever-dwindling reward.5 (If you want to learn more about leptin resistance and obesity, read my book Fat Chance: Beating the Odds Against Sugar, Processed Food, Obesity, and Disease). Furthermore, some people have genetic reasons for their obesity: their NAs are larger, and functional MRI shows that their NAs light up more in response to food commercials than do those people whose weights are normal,6 thus driving increased interest in food.
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Not only is where you are on the curve important, but how much of a dopamine signal you can generate will also impact your motivation response. There are three separate modes of regulation to the dopamine pathway, and any one of them can go haywire, skewing you to the left or to the right of the bell-shaped curve, affecting your mood and behavior. (1) Synthesis. Dopamine is made or synthesized in neurons of the VTA from the amino acid tyrosine, found in many foods (Fig. 3-2).
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Ideally, the dopamine concentration in the VTA is tightly regulated and balanced. Too much dopamine can cause a myriad of problems, including psychotic symptoms. Doctors once used drugs to reduce dopamine synthesis in schizophrenic patients. While successful in ameliorating symptoms of outlandish thought, the drugs also caused patients to feel severely depressed, and ultimately these medications were removed from the market. Doctors have also used drugs that increase dopamine production and/or its release in order to treat chronic depression. This has proved to be helpful in some patients, but side effects for others include irritability, aggression, and paranoia.
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Fig. 3-2: Dopamine synthesis and metabolism. The amino acid tyrosine is acted on by the enzyme tyrosine hydroxylase and receives a hydroxyl group to form L-DOPA. Next, the enzyme DOPA decarboxylase cleaves off a carboxyl group to form dopamine. Dopamine is cleared by the enzymes monamine oxidase (MAO) and catechol-O-methyl transferase (COMT).
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(2) Action. After dopamine (the key) is released from the VTA axonal nerve terminal, it travels across the synapse, where it binds to a dopamine receptor (the lock) on the NA neuron, and excites it, causing the NA neuron to fire, thus generating reward. The number of receptors determines the magnitude of the reward. More functional dopamine receptors mean more chance that any given dopamine molecule will find a receptor to bind to, and therefore more reward signaling even in the face of less dopamine released. Like extreme couponing, ideally you get more for less. But if the number of receptors is reduced, then each dopamine molecule has less chance of finding a receptor to bind to, and therefore will generate less reward. This is a non-specific phenomenon known in medicine as the law of mass action,8 designed to limit each cell’s exposure and vulnerability to chronic stimulation (see Chapter 4). It keeps everything in check. Things that change the receptor number, like genetics and drugs, will influence your position on the bell-shaped curve.
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Some people harbor an alteration in the gene of their dopamine receptors, making them less able to generate the same level of reward. As an example, Eric Stice at Oregon Research Institute has studied the eating habits of patients who harbor the TaqA1 allelic variation of a dopamine receptor, which means that they possess 30 to 40 percent fewer receptors than the rest of the population.9 They need more dopamine in the synapse to occupy fewer receptors, so they need a greater amplitude of motivation to derive any reward from it. And as you might expect, their dopamine receptor number inversely relates to their eating behaviors and their weight gain; fewer receptors means more food intake is necessary to generate any reward, and therefore more weight gain. They need more of a fix to generate the same level of reward as people without this particular genetic variation. Alternatively, the dopamine receptors can be blocked by drugs, so that the dopamine released across the synapse never reaches its target. This is how the dopamine antagonists work. In the 1950s the original anti-psychotic drugs, such as chlorpromazine (Thorazine) and haloperidol (Haldol), revolutionized psychiatry. Up to that point, schizophrenics (1 percent of the population) required long-term or permanent stays in psychiatric wards or care facilities. The dopamine antagonists reintegrated many patients back into society. But these early drugs had severe side effects, such as tardive dyskinesia (uncontrolled movements of the body). The newest generation of antipsychotics, including risperidone (Risperdal), olanzapine (Zyprexa), and aripriprazole (Abilify), have managed to eliminate many of those adverse effects. These medications are often prescribed to adults to enhance the effects of their antidepressants. They are also prescribed as mood stabilizers in irritable children with aggressive and disruptive behavioral disorders (such as autism, ADHD, obsessive-compulsive disorder, and Tourette’s syndrome). But they have some of their own side effects. One possible side effect of their use is a flat affect: they can walk around with little motivation or personality in a Stepford-like haze. These drugs can also induce insulin resistance in the liver, driving insulin levels up, and with it, weight gain.10 Almost every week in my pediatric obesity clinic, I see a child under ten who started their weight gain only when their doctor placed them on one of these mood stabilizers to prevent classroom disruptions.
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(3) Clearance. Dopamine is released into the synapse, where it may or may not occupy its receptor (the key turns the lock; the fewer the receptors, the less likely the occupancy). Party’s over, lights out, call the Uber driver; it’s now time for the mop-up. The dopamine needs to be cleared out of the synapse, which occurs through one of two mechanisms: (a) The dopamine molecules can be recycled and used again. They can be brought back to the neuron that released them, repackaged into little storage vesicles, and put back into play for the next party. This is the function of the dopamine transporter, or DAT.11 Your DATs are akin to the childhood game Hungry Hungry Hippos. They transport and suck dopamine back into the nerve terminal, removing it from the synapse and readying it for the next stimulus. One way to alter the function of the DAT is with various drugs. This is how cocaine acts, by binding irreversibly to the DAT and taking it out of commission. Your first bump of cocaine heightens sensation (kind of like what foreplay does), but it doesn’t last very long, leaving you wanting more. The DAT is also where methamphetamine (crystal meth) acts, by fooling the DAT into trying to transport it, instead of the dopamine.12 Either way the overflow means more dopamine in the synapse, triggering more motivation, more aggressiveness, and more movement. The next time you see someone in the subway snapping their fingers and picking their face, don’t ask them how their dopamine is doing—just know that’s what’s doing. But the DAT can also be a target of drug therapy for ADD or depression or hypersomnia, as this is where methylphenidate (Ritalin) and bupropion (Wellbutrin) and modafinil (Provigil) also work to increase motivation, but without the face picking.
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(b) Alternatively, dopamine molecules can be deactivated by two enzymes called monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) (Fig. 3-2). These enzymes are your personal Pac-Mans, and they gobble up the dopamine and remove the chemical from the synapse entirely. When the dopamine is either recycled or deactivated, the wanting is extinguished. Conversely, dopamine levels in the synapse can be raised by using drugs that inhibit MAO (e.g., phenelzine [Nardil], or one of the original antidepressants), which means less deactivation, more dopamine, more anticipation of reward, and more motivation. When the DATs and MAO/COMT enzymes (hippos and Pac-Mans) aren’t functioning properly due to genetics or illicit drugs, your bell-shaped curve skews to the right. With reduced clearance, more dopamine hangs out in the synapse, meaning more activation at the dopamine receptor and all the baggage that comes with it (see Chapter 5). Unfortunately, your DATs and MAO/COMT enzymes are not very good at determining if you are on your way to, or coming home, from the party. Conversely, if they are too active, they can remove dopamine from the synapse before it ever reaches its destination. Less dopamine, or less binding to receptors, means less motivation and reward.
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Recreational drugs, such as cocaine, are the quickest way to boost your dopamine. But drugs aren’t the only way to access reward, and drug use isn’t the only manifestation of a disordered reward pathway. Humans exhibit a slew of behaviors that can accomplish the same effect on dopamine transmission, generating the same rush that can be just as acutely satisfying. Unfortunately, some of these can quickly become addictive behaviors, and can get you into the same long-term kind of trouble.
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But dopamine is just the gateway neurotransmitter, the trigger. Dopamine is akin to the foreplay before sex (which also releases dopamine): the experience isn’t quite complete until the consummation, the euphoria, the pleasure—which is mediated through another set of chemicals, the endogenous opioid peptides (EOPs), whose cell bodies are in the hypothalamus, the brain area that controls hormones and emotions.15 The most famous of these is beta-endorphin, the brain peptide with properties similar to morphine. It binds to the same opioid receptor as does morphine or heroin, generating the pleasure signal in the nucleus accumbens (NA). The opioids are the business end of the reward pathway, and you can get there with opiate drugs such as hydrocodone (Vicodin) or oxycodone (OxyContin), or with your own beta-endorphin, which is released in response to vigorous exercise. This is what elite athletes try to achieve with long-distance running, to get that runner’s high.16 It has been shown that the pain relief associated with acupuncture is due to EOPs being released in the reward center. EOPs and opiate drugs bind to their receptors to create the sensation of pleasure. But guess what? Just like with dopamine, those EOP receptors are also down-regulated with chronic exposure, to limit their action as well (see Chapter 5), although we’re not sure what happens with runners.
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First the motivation, then the consummation. First the desire, then the pleasure. But that’s assuming that your brain already knows what’s coming. Our behaviors that typify motivation and consummation are pretty much the same from person to person, but the experiences that trigger them are as individual as you are. What floats your boat may sink someone else’s, and vice versa. But you don’t know what trips your trigger till you’ve cocked the pistol. You don’t know what you like or want or need until you’ve experienced it firsthand—at least once. Take a rat naïve to cocaine, morphine, or sugar and implant a recording electrode into the VTA. Then give it a lever for drug administration. Prior to the first exposure, the rat doesn’t care about the lever and those dopamine neurons are quiet. But after that first hit, the reward signal is registered and that neuron is now primed for action. After that, just provide a cue (like the golden arches of McDonald’s) and those dopamine neurons will now fire at fever pitch.17 The rat will push that lever nonstop.
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The goal of reward is not in the motivation; it’s in the consummation. Activating those opioid receptors is where the action is. Pleasure is the goal. Desire is the driver. Motivation drives the outward behavior; consummation is the inward expression of reward.
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Let me give you an example of how the reward pathway works for us—and against us. As I’m writing this, I’m in an Airbnb apartment in Paris (I know, rough draw, but somebody’s got to do it), but it’s August, it’s 95 degrees Fahrenheit with 90 percent humidity, it’s a three-hundred-year-old building, and there’s no air-conditioning and no ventilation. I’m sticky and I’m stuck in this flat writing, waiting for my wife to return from the Louvre with our kids. Right now I’m thinking of a grande coupe of chocolate ice cream. That’s my dopamine telling me to go down to the patisserie on the corner to get a big bowlful, because I deserve it. I could instead get a bottled water to correct my dehydration and to reduce my body temperature somewhat. Cold water can fix my physiology, but I’m not in this for physiology. I’m in this for reward. I’m writing, I’m stressed, I’m hot—and I really want some ice cream. I don’t need it, but I want it—and bad. That’s motivation—that’s the dopamine talking. I order two scoops—the hazelnut and the pistachio (chocolate is so Americain, I decide). Upon my first bite, I get this amazing feeling approaching gustatory nirvana. That’s the beta-endorphin, now giving me my food orgasm in my NA. I’m tempted to order a third scoop, but abstain. My wife returns from her excursion through the Renaissance and says, “Two scoops? Really?” At least I didn’t get three—would I have gotten 50 percent more pleasure from three than from two? More to the point, did I get double the pleasure from two than I would have had from one? That was the cortisol from the stress, shifting my dose-response curve to the right—a very common sequel to the motivation-consummation paradigm, which yields even more untoward effects than the ice cream itself (see Chapter 4). What is my reaction to my wife’s disdain? More cortisol from stress and a rightward shift on the bell-shaped curve. Time for a chocolate croissant.
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EOPs are also designed to shut down further dopamine transmission to the NA, because, ideally, once your reward has been consummated, you don’t need any further anticipation. Cock the trigger, fire the bullet, hit your target, and win the stuffed animal at the fair. Unless … you never hit the target. This happens if the signal of either the dopamine or the EOPs isn’t effectively transmitted at the NA because of chronic overstimulation and reduction of dopamine receptor number. This leaves you wanting (or even needing) more, and more, and more to get even less of an effect. And the decidedly modern phenomenon impacting our dopamine more than anything else? Chronic stress.