Reward and Punish: Say Hello to Dopamine’s Leetle Friend

  Dopamine recruits a helper to track drug rewards.

Ah, dopamine. Whenever it seems like researchers have finally gotten a bead on how that tricky molecule modulates pleasure and reward, and the role it plays in the process of drug and alcohol addiction, along come new findings that rearrange its role, deepening and complicating our understanding of brain function.

We know that the ultimate site of dopamine activity caused by drugs is the ventral tegmental area, or VTA, and an associated structure, the nucleus accumbens. But dopamine neurons in the VTA actually perform two distinct functions. They discriminate acutely between the expectation of reward, and the actual reward itself. Pavlov showed how these dual functions are linked, but the manner in which dopamine neurons computed and then dealt with the differences between expectation and reward—a controversial concept known as reward prediction error—was not well understood.

We all know about reward and punishment, however. Years ago, behaviorism’s emphasis on positive and negative reinforcement demonstrated the strong connection between reward, punishment, and learning. As Michael Bozarth wrote in “Pleasure Systems in the Brain,” addictive drugs “pharmacologically activate brain reward mechanisms involved in the control of normal behavior. Thus, addictive drugs may be used as tools to study brain mechanisms involved in normal motivational and reward processes.”

But how does the evolutionary pursuit of pleasure or avoidance of punishment that guarantees the survival of an organism—fighting, fleeing, feeding, and… fornicating, in the well-known “4-F” configuration—become a pathological reversal of this function? To begin with, as Bozarth writes, “the direct chemical activation of these reward pathways does not in itself represent any severe departure from the normal control reward systems exert over behavior…. Simple activation of brain reward systems does not constitute addiction!”

What does, then? Bozarth believes addiction results from “motivational toxicity,” defined as deterioration in the “ability of normal rewards to govern behavior.” In an impaired reward system, “natural” rewards don’t alter dopamine function as strongly as drug rewards. “Direct pharmacological activation of a reward system dominates the organism’s motivational hierarchy at the expense of other rewards that promote survival,” Bozarth writes. The result? Drug addicts who prefer, say, methamphetamine to food.

How does an addict’s mind become so addled that the next hit takes precedence over the next meal? A group of Harvard-based researchers, writing in Nature, thinks it may have a handle on how the brain calculates reward expectations, and how those calculations go awry in the case of heavy drug and alcohol use.

The dopamine system somehow calculates the results of both failed and fulfilled expectations of reward, and uses that data in future situations. Cellular biologists, with some exceptions, believe that dopamine neurons effectively signal some rather complicated discrepancies between expected and actual rewards. Dopaminergic neurons were, in effect, computing reward prediction error, according to the theory. They were encoding expectation, which spiked when the reward was better than expected, and fell when the reward was less than expected. As Scicurious wrote at her blog, Neurotic Physiology “If you can’t predict where and when you’re going to get food, shelter, or sex in response to specific stimuli, you’re going to be a very hungry, chilly and undersexed organism.” (See her excellent and very readable post on dopamine and reward prediction HERE. )

But nobody knew how this calculation was performed at the cellular level.

Enter research mice.

As it turns out, dopamine is not the whole story. (A single neurotransmitter rarely is.) Dopaminergic neurons account for only about 55-65% of total neurons on the VTA. The rest? Mostly neurons for GABA, the inhibitory transmitter. “Many addictive drugs inhibit VTA GABAergic neurons,” the researchers note, “which increases dopamine release (called disinhibition), a potential mechanism for reinforcing the effects of these drugs.” By inhibiting the inhibitor, so to speak, addictive drugs increase the dopamine buzz factor.

The researchers used two strains of genetically altered mice, one optimized for measuring dopamine, the other for measuring GABA. The scientists conditioned mice using odor cues, and offered four possible outcomes: big reward, small reward, nothing, or punishment (puff of air to the animal’s face). Throughout the conditioning and testing, the researchers recorded the activity of neurons in the ventral tegmental area. They found plenty of neurons with atypical firing patterns. These neurons, in response to reward-predicting odors, showed “persistent excitation” during the delay before the reward. Others showed “persistent inhibition” to reward-predicting odors.

It took a good deal of sorting out, and conclusions are still tentative, but eventually the investigators believed that VTA dopamine neurons managed to detect the discrepancy between expected and actual outcomes by recruiting GABA neurons to aid in the dendritic computation. This mechanism may play a critical role in optimal learning, the researchers argue.

Furthermore, the authors believe that “inhibition of GABAergic neurons by addictive drugs could lead to sustained reward prediction error even after the learned effects of drug intake are well established.” Because alcohol and other addictive drugs disrupt GABA levels in the brain’s reward circuitry, the mechanism for evaluating expectation and reward is compromised. GABA, dopamine’s partner in the enterprise, isn’t contributing properly. The ability to learn from experience and to accurately gauge the likelihood of reward, so famously compromised in active addiction, may be the result of this GABA disruption.

Naoshige Uchida, associate professor of molecular and cellular biology at Harvard, and one of the authors of the Nature paper, said in a press release that until now, “no one knew how these GABA neurons were involved in the reward and punishment cycle. What we believe is happening is that they are inhibiting the dopamine neurons, so the two are working together to make the reward error computation.” Apparently, the firing of dopamine neurons in the VTA signals an unexpected reward—but the firing of GABA neurons signals an expected reward. Working together, GABA neurons aid dopamine neurons in calculating reward prediction error.

In other words, if you inhibit GABA neurons through heavy drug use, you screw up a very intricate dopamine feedback loop. When faced with a reward prediction error, such as drug tolerance—a good example of reward not meeting expectations—addicts will continue taking the drug. This seems nonsensical. If the drug no longer works to produce pleasure like it used to do, then why continue to take it? It may be because dopamine-active brain circuits are no longer accurately computing reward prediction errors. Not even close. The research suggests that an addict’s brain no longer registers negative responses to drugs as reward errors. Instead, all that remains is the reinforcing signals from the dopamine neurons: Get more drugs.

[Tip of the hat to Eric Barker (@bakadesuyo) for bringing this study to my attention.]

Cohen, J., Haesler, S., Vong, L., Lowell, B., & Uchida, N. (2012). Neuron-type-specific signals for reward and punishment in the ventral tegmental area Nature DOI: 10.1038/nature10754

Photo Credit: http://www.zazzle.com 

Liking It Vs. Wanting It

The Joylessness of Drug Addiction.

Hedonism, the pursuit of pleasure for its own sake, is not really the answer to the riddle of drug addiction. The pursuit of pleasure does not explain why so many addicts insist that they abuse drugs in a never-ending attempt to feel normal. With compulsive use and overuse, much of the pleasure eventually leaches out of the primary dysphoria-relieving drug experience. This does not, however, put an end to the drug-seeking behavior. Far from it. This is the point at which non-addicts tend to believe that there is no longer an excuse—the pleasure has dribbled away, the thrill is gone—but even when addicts aren’t getting the full feel-good benefits of the habit, they continue to use.

And now we know why. Any sufficiently powerful receptor-active drug is, in its way, fooling Mother Nature. This deceit means, in a sense, that all such drugs are illicit. They are not natural, however organic they may be. Yet, the human drive to use them is all-pervasive. We have no real built-in immunity to drugs that directly target specific receptors in the limbic and cortical pleasure pathways. 

The act of “liking” something is controlled by the forebrain and brain stem. If you receive a pleasant reward, your reaction is to “like” it. If, however, you are anticipating a reward, and are, in fact, engaging in behaviors motivated by that anticipation, it can be said that you “want” it. The wholly different act of wanting something strongly is a mesolimbic dopamine-serotonin phenomenon. We like to receive gifts, for example, but we want food, sex, and drugs. As Nesse and Berridge  put it, “The ‘liking’ system is activated by receiving the reward, while the ‘wanting’ system anticipates reward and motivates instrumental behaviors. When these two systems are exposed to drugs, the “wanting” system motivates persistent pursuit of drugs that no longer give pleasure, thus offering an explanation for a core paradox in addiction.” 

The absence of pleasure does not mean the end of compulsive drug use. Researchers are beginning to understand how certain drugs can be so alluring as to defeat the strongest of people and the best of intentions. It certainly does not eliminate the pain of drug hunger, of craving, to know that it is physically correlated with “a pathological overactivity of mesolimbic dopamine function,” combined, perhaps, with “increased secretion of glucocorticoids.” For such a wide variety of drugs, exhibiting a wide variety of effects, the withdrawal symptoms, while varying by degree, are nonetheless quite similar. The key, as we have seen, is that the areas of the brain that control “wanting” become sensitized by reward pathway drugs.

Under the biochemical paradigm, a runaway appetite for non-stop stimulation of the reward pathway is a prescription for disaster. The harm is physical, behavioral, and psychological—as are the symptoms. Peer pressure, disciplinary difficulties, contempt for authority—none of these conditions is necessary for drug addiction to blossom. What the drug itself does to people who are biologically vulnerable is enough. No further inducements are required. 

Graphics Credit: http://rmcute.multiply.com/

What’s a Neurotransmitter, Anyway?

A brief guide for the perplexed.

A neurotransmitter is a chemical substance that carries impulses from one nerve cell to another. Neurotransmitters are manufactured by the body and are released from storage sacs in the nerve cells. A tiny junction, called the synaptic gap, lies between brain cells. (Think of Michelangelo’s Sistine Chapel, with the finger of Adam and the finger of God not quite touching, yet conveying energy and information.)

Neurotransmitters squirt across the synaptic gap, and this shower of chemical messengers lands on a field of tiny bumps attached to the surface of the nerve cell on the other side of the synaptic gap. These bumps are receptors, and they have distinctive shapes. Picture these receptors, brain researcher Candace Pert has suggested, as a field of lily pads floating on the outer oily surface of the cell.

Neurotransmitter molecules bind themselves tightly to these receptors. The fact that certain drugs of abuse also lock tightly into existing receptors, and send messages to nerve cells in the brain, is the key to the mystery of addiction.

The fact that certain drugs essentially “fool” receptors into receiving them is one of the most important and far-reaching discoveries in the history of modern science. It is the reason why even minute amounts of certain drugs can have such powerful effects on the human nervous system. The lock-and-key arrangement of neurotransmitters and their receptors is the fundamental architecture of action in the brain. Glandular cells are studded with receptors, and many of the hormones have their own receptors as well. If the drug fits the receptor and elicits a response, it is called an agonist. If it simply blocks the receptor site without stimulating a response, it is an antagonist. Still other neurotransmitters have only a secondary effect, causing the target cell to release other kinds of neurotransmitters and hormones.

Two of the most important neurotransmitters are serotonin and dopamine. The unfolding story of addiction science, at bottom, is the story of what has been learned about the nature and function of such chemicals, and the many and varied ways they effect the pleasure and reward centers in our brains.

In 1948, three researchers—Maurice Rapport, Arda Green, and Irvine Page—were looking for a better blood pressure medication. Instead, they managed to isolate a naturally occurring compound in beef blood called serotonin (pronounced sarah-tóne-in), and known chemically as 5-hydroxytryptamine, or simply 5-HT. The researchers determined that serotonin was involved in vasoconstriction, or narrowing of the blood vessels, and in that respect resembled another important chemical messenger in the brain—epinephrine, better known as adrenaline.

Even though there is at most 10 milligrams of the substance in our bodies, serotonin turned out to be one of nature’s signature chemicals—a chemical of thought, movement and behavior, as well as digestion, ejaculation, and evacuation. The body’s all-purpose neurotransmitter, involved in sleep, mood, appetite, among dozens of other functions. The cortex, the limbic system, the brain stem, the gut, the genitals, the bowels: serotonin is a key chemical messenger in all of it.

Another key neurotransmitter—dopamine—is considered to be one of the brain’s primary “pleasure chemicals,” and is found in areas of the brain linked to experiences of joy and reward.

Dopamine pathways play a role in carrying signals related to attention, movement, problem solving, pleasure, and the anticipation of rewarding experiences. Dopamine is one of the reasons why, after you have a pleasurable experience with food, drink, sex, or certain drugs, you are likely to feel a desire to repeat the experience. Dopamine is implicated in not just the drug high, but in the craving that accompanies withdrawal as well.

Feelings of pleasure, or joy, are natural drug highs. The fact that they are produced by chemical alterations in brain state does not make the fear or the pleasure feel any less real.

Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008


Photo Credit: NIDA

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Serotonin and Dopamine: A Primer

The Molecules of Reward

Serotonin and dopamine are part of a group of compounds called biogenic amines. In addition to serotonin and dopamine, the amines include noradrenaline, acetylcholine, and histamine. This class of chemical messengers is produced, in turn, from basic amino acids like tyrosine, tryptophan, and choline. The amines are of great interest, because both mood-altering drugs and addictive drugs show a very straightforward affinity for receptors sites designed for endogenous amines.

Addictive drugs have molecules that are the right shape for the amine receptors. Drugs like LSD and Ecstasy target serotonin systems. Serotonin systems control feeding and sleeping behaviors in living creatures from slugs to chimps. Serotonin, also known as 5-HT, occurs in nuts, fruit, and snake venom. It is found in the intestinal walls, large blood vessels, and the central nervous system of most vertebrates. The body normally synthesizes 5-hydroxytryptamine, as serotonin is formally known, from tryptophan in the diet.

Thus far, no other substance found the central nervous system has as many diverse receptor actions as 5-HT. The average adult has only about 10 milligrams of serotonin in his or her body. It is involved, to one degree or another, in appetite, sleep, mood, memory, learning, endocrine regulation, smooth muscle contractions, migraine headaches, motility of the GI tract, blood platelet homeostasis, so on. Serotonin also plays a large role in initiating and shaping certain kinds of behavior, especially behaviors of a sexual or hallucinatory nature. In animal models, lower serotonin levels correlate with higher levels of violence.

A receptor-selective agent like Sumatriptan, a popular migraine medication, works by binding selectively to a serotonin receptor subtype involved in arterial circulation and dilation. The difference between serotonin-active drugs like sumatriptan, and similarly serotonin-active drugs LSD or Ecstasy, is that the former locks exclusively into these “5-HT1” receptors, and nowhere else. The ergot alkaloids are all over the serotonin system, causing general surges of their own.

Psychedelic drugs like LSD and Ecstasy (chemically known as indoleamines) and mescaline (phenethylamines) make up the two major classes of hallucinatory drugs. They are both partial agonists at 5-HT receptors, boosting serotonin particularly in the cerebral cortex and the locus coeruleus. There is also some enhancement of glutamine activity as well. Other 5-HT agonists, like ondansetron (trade name Zofran), do not have that effect. Ondansetron helps block the nausea of chemotherapy by blocking serotonin activity in the GI tract. Vomiting is a serotonin-mediated reflex. In this case, it is the 5-HT3 receptor subtype that is of note. Ondansetron’s selective affinity for that subtype makes it a useful anti-emetic.

Dopamine, like serotonin appears to be strongly involved in mediating craving-- drug hunger, as well as real hunger. This yields a partial answer to one of addiction’s mysteries: Why would a drug addict, an alcoholic, continue to use when the adverse effects of continued use have long ago swamped whatever euphoric sense of well being, or even just plain normalcy, that once was obtained through the drug? One answer might be that dopamine causes human beings to pay attention to stimuli that are potentially rewarding. Even in the absence of any possibility of reward--on a desert island, in a rehab clinic--dopamine dysregulation could kindle episodes of fierce craving, because such episodes had led in the past to a renewed ingestion of the drug in question-- all the fiercer, these cravings, this drug hunger, whenever the addict was exposed to direct cues, like seeing the drug, or being in places where the addict had used before.

Scientists have managed to record a rise in dopamine levels in lab rats simply by cueing the rats to anticipate a pleasurable event--food, sex, sweet drinks. For example, you could condition the rats to a ringing bell before dinner, and soon the rats would be showing elevated dopamine levels at the sound of the bell only--with no reward at all. Anticipation of reward was all it took. Or you could give one of the male rats a good close look at a suitable female through a mesh panel, and the male rat’s dopamine levels would surge, presumably in anticipation of possible carnal pleasures, and dopamine levels would spike even higher, of course, once the divider was removed.

Serotonin/dopamine dysfunctions cause physical discomfort, anxiety, and panic--what a renowned neuropharmacologist has termed “spiraling distress”—which continues to occur even in the complete absence of the addictive drug. Take the drug away, and the brain begins its complex and minutely ordered repertoire of compensatory effects--unpleasant sensations as read out by the addict.

Finding a way to override serotonin- and dopamine-mediated mid-brain commands is one of the keys to recovery from addiction. One of the aims of a biological understanding of addiction is to tease out the mechanisms by which the reinforcing effects of addictive drugs become transformed into long-term adaptive changes in certain areas of the brain. “Why are we so surprised that when you take a poison a thousand times, it makes some changes in your head?” wondered James Halikas, who was co-director of the chemical dependency treatment program at the University of Minnesota during the crack heyday of the late 1980s and early 1990s. “It makes sense that poisons change things.”

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