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.
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. 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.
Can I Get a Double?
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. Over the past thirty years, due to the coming of age of some novel biochemical, molecular biological, pharmacological, and imaging techniques, scientists have been able to piece together the drivers and the business end of the reward system, and understand how it can be manipulated for good (and for bad).
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.
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). 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.
Graded on a Bell-Shaped Curve
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. Let me give you two examples.
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. 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 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.
(2) Estrogen. At least half of all women will tell you that their menstrual cycles make them hormonal, playing havoc with their level of performance on simple tasks and their working memory. Rising estrogen means rising dopamine. At the time of ovulation, when estrogen level is at its peak, women can
be either focused and motivated, checking things off their to-do lists, or on the verge of maiming their family members for forgetting to pick up the ice cream. Who’s who and why? Which are you? Depends on where you start on the dopamine bell-shaped curve, which is likely predetermined by genetics. Around 25 percent of women start on the left side of the curve because they have the Val158Val genotype (the combination of genes on each set of chromosomes in each cell) of the protein that chews up dopamine, meaning they have less dopamine hanging around, especially in the prefrontal cortex, which is the executive planning and rational part of the brain. When their estrogen rises before ovulation, it actually shifts them to their optimal level on the curve, and they become clearer and sharper.7 Another 25 percent of women spend the majority of the month at their optimum dopamine levels on the curve. That boost in estrogen at ovulation pushes them farther to the right of the curve, which can cause befuddlement, irritability, and aggression. So if your girlfriend snaps at the smallest provocation on a monthly basis (when she’s ovulating, and assuming she’s not on birth control), it may be due to her having the Met158Met genotype instead.
Get a Hit, Get a Rush
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). 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. Medications affecting dopamine production are still being researched to help patients find that sweet spot on the bell-shaped curve.
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).
(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.
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.
(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 it. 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.
(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 anti
depressants), 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.
Too Much of a Good Thing
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. Perhaps the behavior we have the most data on is gambling.13 The excitement of the Kentucky Derby is unmistakable: it’s an annual no-miss event at our house. It generates the same dopamine rush, to different extents, as a ski run down a steep slope, a shopping spree at Saks Fifth Avenue, or a line of cocaine.14 One spin of the roulette wheel doesn’t make you a compulsive gambler, just as one bump of cocaine doesn’t make you an addict. But one dopamine rush often turns into two, and in virtually no time you just might resemble Sky Masterson from the stage musical Guys and Dolls (1950), betting the farm on which raindrop will reach the windowsill first.
The Hacking of the American Mind Page 5