Part 6 (2/2)

We all know, however, that a fitness indicator that is useful at one point in historical time may not be useful at another time if the environment in which natural selection takes place changes dramatically. For example, in earlier chapters we learned that our intrinsic fondness for sweets in the forms of fructose and lactose serves an important function of feeding the metabolic machinery of each cell in our body. This fondness, which was forged by selection pressures in our prehistoric hunter-gatherer days, has turned into a pathological condition in modern environments with the advent of refined sugars. It now contributes to a number of modern health problems, including obesity, diabetes, and heart disease, to name just a few.

While this particular example makes sense, one might ask how this general process extends to a fondness for drugs or alcohol. Lactose and fructose were clearly available in our hunter-gatherer days, so it was at least possible that they might be used as selection factors. Those who could identify and consume these resources stood a better chance at surviving to reproductive age. But were alcohol and other psychoactive compounds available? Certainly we can't expect the synthetic forms we have today to have existed during hunter-gatherer times, but what about their precursors? If such substances did not exist during ancestral times, they never could have been used as selection factors, and hence an evolutionary theory of addiction based on the hedonic model would not make much sense.

People often think psychoactive drugs are modern phenomena; they are not. They are a modern problem, to be sure, but their precursors have coevolved with hominoids through the millennia. Many anthropologists have pointed out that h.o.m.o sapiens h.o.m.o sapiens have enjoyed a coevolutionary relations.h.i.+p with psychotropic plants for millions of years. In this coevolutionary arms race, mammals have evolved mechanisms to metabolize certain plant substances, and at the same time, plants have evolved toxins that mimic the chemical structure of many endogenous neurotransmitters and neuropeptides. For instance, have enjoyed a coevolutionary relations.h.i.+p with psychotropic plants for millions of years. In this coevolutionary arms race, mammals have evolved mechanisms to metabolize certain plant substances, and at the same time, plants have evolved toxins that mimic the chemical structure of many endogenous neurotransmitters and neuropeptides. For instance, Areca catechu Areca catechu, commonly known as betel nut, was being used at least thirteen thousand to fifteen thousand years ago in ancient Timor. You have probably never heard of betel nut, but it is currently the fourth most commonly used drug on the planet following nicotine, ethanol, and caffeine.There is also evidence that nicotine was being extracted from pituri plants by indigenous Australians in Queensland some forty thousand years ago.

An open question concerns how and when these substances were used. For many psychoactive substances, there is archaeological evidence that they were used in ceremonial contexts, but there is also evidence that they were simply everyday food sources and used for medicinal purposes. Our relations.h.i.+p with alcohol probably goes back even farther than the drugs just mentioned. Virtually every species that ingests fermenting fruit is subject to low levels of ethanol exposure. Indeed, the anthropoid diet has been predominantly frugivorous (fruit-eating) for some forty million years, suggesting that ethanol exposure is old and prevalent in our prehistory. Temperate-zone fruit sources have been shown to manifest ethanol concentrations ranging from 0 to 12 percent. Comparative studies have found that as most temperate fruit ripen, both their ethanol and natural sugar contents increase. Consequently, mammals that were consistently able to identify and consume fruits enjoyed the fitness benefits of fructose, but also ingested low levels of ethanol as part of their diet. Some anthropologists have suggested that ethanol plumes may have even been used by early mammals to identify fermenting fruit, making the identification of environmental ethanol a fitness indicator. Regardless of their use, hominids have clearly had a long relations.h.i.+p with plant-derived psychoactive compounds.

At this point we know three very important things. First, psychoactive substances were likely consumed quite commonly in ancestral environments. Second, mammals have evolved distinct mechanisms for detecting and consuming these substances. Third, these substances may have had fitness value in the form of medicines, food supplements, or a means to find either of the two. Hence our simple two-dimensional hedonic fitness model of emotions may apply to these psychoactive compounds. So how do emotions play a role in addiction? In particular, why does the pleasure instinct nudge some of us toward addiction, but not all of us?

The Many Faces of Vice It is quite popular to experiment with potentially addictive drugs. More than 60 percent of Americans have tried an illicit substance at least once in their lifetime, and if alcohol is included, the number rises to more than 90 percent. But, of course, only a very small percentage of people who actually try a potentially addictive drug become addicted. For instance, recent studies have found that even for a highly addictive drug such as cocaine, only 15 percent of users become addicted within the first ten years of use. The addiction literature often focuses so intently on the particular psychological and biological mechanisms that might be responsible for the addictive process that we seldom ask the simple question as to why so relatively few users ever become addicted. An evolutionary perspective may prove particularly useful in addressing this question, since it a.s.sumes that we are all all susceptible to addiction, not just some of us. Another question that can be addressed from an evolutionary view concerns why there are so many different forms of addiction. Are there psychological or biological mechanisms that are common roots for all forms of addiction, whether the compulsion is to use heroin, eat fried food, or gamble? susceptible to addiction, not just some of us. Another question that can be addressed from an evolutionary view concerns why there are so many different forms of addiction. Are there psychological or biological mechanisms that are common roots for all forms of addiction, whether the compulsion is to use heroin, eat fried food, or gamble?

What are the different kinds of addiction? The answer changes depending on whom you ask. Certainly there are the cla.s.sics that we all typically think of when we talk about chemical addictions such as drugs and alcohol. But what about other activities, such as food, s.e.x, video games, surfing the Internet, thrill-seeking, shopping, and so forth, that may share common points with the more traditional forms? Let us look at the leading theories of what addiction is and how it forms.This will provide greater context for understanding how the pleasure instinct may contribute to the casual use of certain substances and how this use may transition to full-blown addiction.

There is an enormous literature in this area, but three major theories have stood the test of time. Each tries to explain the psychological variables and processes that govern the transition from casual to compulsive substance use. They are: (1) the cla.s.sic hedonic view cla.s.sic hedonic view that drugs are taken for the pleasure they provide the user and that unpleasant withdrawal symptoms are the primary cause of addiction; (2) the that drugs are taken for the pleasure they provide the user and that unpleasant withdrawal symptoms are the primary cause of addiction; (2) the aberrant learning perspective aberrant learning perspective, which holds that addiction results from the formation of pathological stimulus-response a.s.sociations; and (3) the loss of inhibitory control theory loss of inhibitory control theory, which suggests that the brain systems that usually regulate impulsivity may be impaired, resulting in greater susceptibility to substances that provide immediate gratification. I will introduce and contrast these theories with a fourth, the modified or modern hedonic view modified or modern hedonic view, based on recent findings that the neural systems responsible for ”wanting” a drug are different from the systems that control ”liking” a drug.

The cla.s.sic hedonic explanation for addiction dates to the 1940s, but it wasn't until the work of Richard Solomon and his colleagues in the 1970s that formal theories were first developed and tested. The basic idea is that we take drugs because they bring us pleasure. Repeated exposure to the same drug, however, leads to tolerance such that ever-increasing doses are needed to get the same high. The same homeostatic neural mechanisms that lead to tolerance result in withdrawal symptoms if the drug is discontinued. Hence compulsive drug use (addiction) is maintained to avoid the unpleasant withdrawal symptoms.

The central mechanism in this theory is homeostatic in nature. There are hundreds of examples of compensatory responses that operate in living systems. All mammals live most comfortably within a specific optimal range of values for variables such as core body temperature, blood composition, blood pressure, and others. Brain cells, for example, are very temperature-sensitive. Their electrophysiological responsiveness to stimulation changes dramatically with even small deviations from a core body temperature of 37 degrees Celsius.

Cells in the hypothalamus are sensitive to temperature deviations and send feedback signals into the peripheral nervous system to make compensatory adjustments to the rest of your body that are designed to bring body temperature back into the optimal range. If you're a member of the Polar Bear Club and just finis.h.i.+ng a brisk winter swim in Lake Michigan, as you leave the water your hypothalamus will scream at your autonomic nervous system to make adjustments. It will send signals whose end results are to make you s.h.i.+ver (in an attempt to warm the muscles), develop goose b.u.mps (to fluff your nonexistent fur), and turn your skin blue (a result of blood moving away from cold surface tissues to warm the inner sensitive core of the body).

If, on the other hand, you are involved in strenuous exercise on a very warm day, the hypothalamus activates systems to dissipate heat such as perspiration (which cools the skin by evaporation) and increasing blood flow to the skin surface, where heat can be radiated away (and make your face appear flushed). There are many other examples of homeostatic control by the hypothalamus and other brain regions, including the regulation of blood oxygen, volume, salinity, acidity, and so forth.

Ingestion of a drug that binds with brain receptors does the same thing as environmental changes do in the examples given above. It causes a s.h.i.+ft in normal neurotransmission that will, in turn, elicit compensatory mechanisms that attempt to bring the system back to some rough homeostatic or allostatic level. But the compensatory response actually competes with the drug-induced response. This process results in users needing to increase their dosage to get the same effect.This is known as drug tolerance.When drug ingestion is stopped, the compensatory response is still active, so there is a net s.h.i.+ft toward effects in the opposite opposite direction of those induced by the drug. These effects operate at a number of levels and comprise the symptoms a.s.sociated with withdrawal. Thus at the sensory level, the pleasure induced by drug ingestion is combated by unpleasant opposing processes that are left unchecked during the withdrawal state. direction of those induced by the drug. These effects operate at a number of levels and comprise the symptoms a.s.sociated with withdrawal. Thus at the sensory level, the pleasure induced by drug ingestion is combated by unpleasant opposing processes that are left unchecked during the withdrawal state.

Although the cla.s.sic hedonic model is appealing for a number of reasons, experimental and observational findings suggest that it is limited in accounting for several aspects of the addictive process. One problem with the theory is that it fails to explain why individuals addicted to drugs often relapse into use even after they are free of withdrawal symptoms.The compensatory response that underlies withdrawal decays over time, and therefore the supposed prime reason for continued use no longer exists. Another major problem for the theory is that many addictive substances are not terribly pleasant at first, yet they still drive compulsive behaviors. If there is no hedonic value from the start, why would use continue beyond the first neutral or even negative experience? A typical example of this effect is first-time cigarette use, which most people find very unpleasant.

Aberrant learning theory is probably the newest perspective on addiction. The basic idea is grounded in a.s.sociative learning theory (see chapter 3), where a stimulus and a response become paired. Experiments in rodents have shown that distinct parts of the brain become activated when an animal is rewarded with an addictive drug (for example, the nucleus acc.u.mbens, a collection of neurons in the forebrain) and often in antic.i.p.ation (for example, the medial prefrontal cortex) of the reward.There are endogenous brain receptors for all psychoactive compounds. For instance, mu receptors are activated by morphine and heroin, and dopamine receptors are activated by cocaine and amphetamines.We, of course, do not have these agents circulating naturally through our bodies, but there are endogenous a.n.a.logues that have evolved as neurotransmitters and neuropeptides.There are a number of ways one can measure the affinity or strength with which a natural neurotransmitter can activate a receptor and trigger the ensuing biochemical process. The aberrant learning theory posits that modern addictive drugs have much greater potency in activating endogenous receptors than their natural counterparts and hence act like an abnormally powerful stimulus. A neural system that is designed to learn stimulus-response pairings will be hyperactivated by such a powerful stimulus, and this learning might be very quick and enduring. The theory suggests, then, that the neural systems that typically regulate positive emotions such as pleasure are fooled by an abnormally powerful stimulus (a pure drug rather than the less potent endogenous counterpart) that essentially hijacks this normal process and creates a false fitness indicator signal.

One limitation of the aberrant learning theory is that there has never been a reasonable explanation as to why an unusually strong stimulus-response a.s.sociation would immutably lead to compulsive behaviors. Since it is still a relatively new perspective, more studies are needed to fill in some of the missing pieces that connect alterations at the neural level to ultimate changes in psychological functioning and behavior.

The third major theoretical perspective on addiction involves the loss of inhibitory control. This perspective is really a much broader theory about the origins of impulsive behaviors and extends well beyond addiction. The famous story of Phineas Gage, a man whose life changed in the blink of an eye, ill.u.s.trates how damage to the brain areas that control impulsivity affects many behaviors that are also altered by addiction.

The year is 1848, and like much of New England, Vermont is slowly stirring from its sleepy agrarian pace toward industrialization. Part of this transformation resides in the construction of several railways that will soon connect the major cities of the region. As one follows the planned route of the Rutland and Burlington line from Bellows Falls northward, the towns.h.i.+p of Duttonsville emerges within just a few miles, and we find ourselves abruptly s.h.i.+fting direction, moving on a westward path toward Proctorsville. It is in this small town that we find Phineas P. Gage, a foreman contracted to lay ties for this segment of our new railway.

Gage is a great favorite with the men in his gang of navigators or navvies, a term left over from the early days when many of the laborers working on the railway found prior employment in the construction of ca.n.a.ls used for transporting goods. The men revere him because he is a diligent worker possessing an iron frame and is scrupulously fair in the way he treats those in his employ. He does not play favorites, but rather allots tasks and pay in an equitable manner.This exacting and decisive nature also makes Phineas a favorite with his employers, who consider him ”the most efficient and capable man” they have.

Indeed, everyone seems to like Phineas Gage. Friends and neighbors describe him as quiet and respectful of others, and such ”temperate habits” are the hallmark of a good foreman. Bosses who fail to live up to these standards are unpopular, and within the culture of violence that persists among the rail workers at present, run the risk of being attacked and possibly killed. Indeed, by the time Gage is at work on the line, several foremen have already been fatally wounded by those in their charge in and around the Cavendish area.

At the moment, Phineas and his gang are laying a portion of the track that smacks snug up against the Black River.They will have to blast away large outcroppings of rock so the line can a.s.sume a level and straight flow. Blasting involves several stages that must be performed carefully and in the correct sequence. After a small diameter hole is drilled, a safety fuse is knotted and placed into the hole. Then an explosive powder, usually made from a mixture of sulfur, charcoal, and a nitrate such as saltpeter, is placed over the fuse. Finally, sand or clay is poured over the powder and compacted with a tamping iron. The purpose of tamping is to consolidate the explosive force to as small an area as possible, thereby allowing the charge to detonate into the rock with greater efficiency rather than escaping ineffectually back out the hole.

Phineas is an old hand at this and has had his tamping iron forged by a local blacksmith to his own specifications-”to please the fancy of the owner,” others would later say. It is 3 feet, 7 inches long, 1 inches in diameter at the larger end, and tapered to a sharp point of -inch diameter at the other end. It is quite hefty, in all weighing almost 13 pounds.

The gang has been at work all day along a bend in the bank of the river, and Phineas has just poured explosive powder into a shallow hole about three feet deep. While waiting for his a.s.sistant to pour sand over the mixture before he tamps the charge, a commotion among the men erupts just a few feet behind him. Looking over his right shoulder, he turns to see that all is okay but must feel every ounce of the full weight of the tamping iron in his hand, for it has been a long day and it is 4:30 P.M., almost quitting time. As he returns his attention to tamp the charge, a shattering explosion occurs, and his iron, sharp side forward, is thrust up, piercing his left cheek. The projectile is moving with such extreme force that it penetrates the base of his skull, plowing through the front portion of his brain, and exits out the top of his head. Phineas immediately falls back to the ground, while his tamping iron, covered in blood, has rocketed an additional hundred yards before returning to earth. Amazingly he is still conscious and begins to speak to those stunned workers gathering around him.

Gage manages to stand awkwardly and ”walks a few rods”-fifty feet or so-to an ox cart, where he rests against the foreboard and is driven the three-quarters of a mile back to his room in town. The cart lurches west past the intersection of Depot and Main streets, and when it arrives at the tavern of Mr. Joseph Adams, owner and solicitor, Phineas walks to the back, allowing two of his men to help him down. He then gently moves a short distance up three stairs and comes to rest in a small chair on the tavern's veranda to await medical attention. It is not until some two weeks later that Phineas emerges from his semiconscious state and begins to stir.

As improbable as the accident and recovery were, and as delighted in his progress as his physicians could be, Gage's friends soon began to realize that something in Phineas was amiss-”Gage is no longer Gage,” several remarked. Within six weeks of the accident, much of the temperament of the young foreman working on the Rutland and Burlington Railroad has now changed.Those things that made Phineas who he was, at least to his friends and family, seem to have been stripped away with the shearing force of the tamping iron. Rather than being described as one who ”possessed a well-balanced mind . . . looked upon by those who knew him as a shrewd, smart businessman, [and] . . . persistent in executing all his plans of operation,” we find a new set of postaccident adjectives used to describe his character.

After recovering his physical strength, Phineas pleaded for his old job as foreman but was turned away. His contractors, who considered him the most efficient and capable man in their employ before the accident, regarded the change in his personality and behavior as so severe that they could not grant him his position again. In a letter to the Ma.s.sachusetts Medical Society, Gage's physician, Dr. John Harlow, writes, ”the equilibrium or balance, so to speak, between his intellectual faculties and animal propensities, seems to have been destroyed. He is fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times perniciously obstinate, yet capricious and vacillating, devising many plans of future operation, which are no sooner arranged than they are abandoned in turn for others appearing more feasible. A child in his intellectual capacity and manifestations, he has the animal pa.s.sions of a strong man.”

The description of the new Phineas as childlike was common among his friends, family, and even his physician. Gone was the man who routinely managed a large gang of navvies with competence and an efficiency that was the envy of other foremen. In his place we find a mercurial man who has no patience for plans or goals, little emotional attachment to previous friends, and seems to have lost the ability to antic.i.p.ate the future and control his impulsive desire to live only in the present.

We now understand that the tamping iron damaged a large portion of Phineas's frontal cortex, an area that we know from experiments in animals and humans is intimately involved in higher cognitive functions, including the ability to balance present needs with longer-term consequences. Rats that have very restricted damage to key neural pathways that link brain areas involved in positive emotions such as the nucleus acc.u.mbens with the prefrontal cortex have impaired learning on a number of tasks. For instance, in one study paradigm rats are given a sweetened treat, but it is accompanied by a mild foot shock. Normal rats typically learn within one or two trials to avoid the treat (even though they would normally consume it readily) and the subsequent foot shock. Rats with damage to this inhibitory pathway, however, go back again and again for the treat despite the repeated foot shock that clearly causes them distress.

There is emerging evidence that chronic exposure to some addictive drugs such as amphetamines and cocaine can reduce neural activation in the frontocortical systems that seem to regulate inhibitory control. Consistent with these findings, addicts often exhibit a very similar pattern of deficits on neuropsychological tests to those observed in patients with damage to frontocortical systems. Taken together, this suggests that individuals who have weakened frontocortical systems may be less able to regulate impulsivity, and this limitation may contribute, in part, to drug-using behaviors.

The loss of inhibitory control and its a.s.sociated behavioral problems seem to be robust phenomena in certain individuals, particularly those with obvious brain damage. It is still very unclear, however, if it is possible that more subtle deficits (perhaps not involving structural damage) in frontocortical functioning would predispose an individual to drug-seeking. It is very likely that a loss of inhibitory control is just one component of the addictive process and may work alongside other mechanisms to drive both drug-seeking and compulsive drug use.

The fourth major theory of addiction is the modern hedonic perspective. This view is rooted in fairly recent findings from a handful of neuroscientists who have shown that there seem to be different neural systems that regulate the ”wanting” of a drug versus the ”liking” of a drug. Kent Berridge and Terry Robinson, working at the University of Michigan, developed what is more formally called the ”incentive sensitization” theory of addiction. In a series of elegant experiments, the researchers delineated two neural systems that contribute to the addictive process in fundamentally different ways.

Experiments in Berridge's lab and those of others have shown that in rats, addictive drugs alter the nucleus acc.u.mbens and related brain circuits that regulate motivational behaviors. If these circuits are lesioned in rats, the animals no longer display normal motivational behaviors such as seeking natural rewards (for example, s.e.x, food, and water). Chemical activation of this circuitry when it is intact facilitates these motivational behaviors.This circuitry is part of the larger mesolimbic dopamine system that involves projections from brainstem regions to a number of pleasure centers such as the nucleus acc.u.mbens, larger striatum, and portions of the frontal cortex (see chapter 3).

For years, scientists thought this was the only brain system involved in reward, but we now know that at least four major systems are responsible for what we colloquially refer to as pleasure. Recent experiments have suggested that the mesolimbic dopamine system is primarily responsible for regulating motivational behaviors that make us ”want” things. For instance, genetic manipulations that create mice with hyperactivated mesolimbic dopamine systems result in animals that are more motivated to obtain rewards and less distracted in reaching this goal than normal everyday mice. A major point, however, is that these animals do not display an enhanced ”liking” of the reward once it is obtained-they don't consume any more than normal mice once they actually have the reward.The incentive sensitization theory holds that repeated use of addictive drugs enduringly alters this brain circuit, which in turn makes the drugs more desirable, resulting in a positive feedback loop. The process is a.n.a.logous to activation of skin histamine receptors that causes us to scratch, thereby leading to further histamine release.

The mesolimbic dopamine system is only part of the hedonic story. The other major component is the brain's opioid system. Injection of chemicals that boost opioid neurotransmission in the basal forebrain markedly increases the actual consumption of palatable foods in rats. Moreover, opioid drugs given to humans and rodents increase their hedonic reactions to sucrose. Working in Berridge's laboratory, Susana Pecina has identified several ”hedonic hot spots” in rats that when activated by opioid agonists enhance their natural pleasurable response to sucrose. Likewise, blocking opioid neurotransmission at these sites decreases the hedonic response or ”liking” of sucrose.

These findings address a key limitation of the traditional hedonic model, namely, why people become addicted to an initially unpleasant experience (such as smoking or ingesting alcohol for some individuals). Indeed, many people who are addicted report that the pleasurable feelings initially felt when first using the drug subsided over time with continued use, yet they still felt strongly compelled to use the drug-they still wanted it, even though they did not necessarily like it. The fact that there are two entirely different neural systems that mediate distinct components of the pleasure instinct helps explain why many times there seems to be a dissociation between wanting a drug and liking a drug.

These components may have very different dynamics during the different states of drug use. Initial drug use, for instance, is most likely mediated by both mesolimbic dopamine circuits and the opioid system (that is, both wanting and liking). The transition to compulsive drug abuse may, in turn, be mediated primarily by the mesolimbic system, since many addicts complain that they do not experience the same hedonic response or ”liking” once addicted as they initially did from the drug. One can further imagine that overactivation of the mesolimbic dopamine system, coupled with disruption to frontocortical inhibitory circuitry that may occur with amphetamine and cocaine use, could result in a particularly dangerous combination where drug wanting is enhanced and inhibitory control is reduced.

Berridge's lab has recently discovered that yet another brain system may help regulate ”liking.” The cannabinoid system (see chapter 6) overlaps in many locations with the opioid system. For instance, both have connections in the nucleus acc.u.mbens, but, of course, utilize different chemical neurotransmitters. Microinjection of the cannabinoid agonist anandamide into the nucleus acc.u.mbens of rats enhances their liking responses to sucrose in the same way as do opioids. Further work is now being done in multiple laboratories to determine how broad the cannabinoid circuitry is and to what extent it overlaps with the other two transmitter systems involved in the pleasure instinct.

Each of these three systems is known to have wide networks that stretch across the entire brain. In addition to the forebrain locations mentioned above, each of the neurotransmitter systems has brainstem sites that seem to play a similar role in the wanting or the liking component of the pleasure instinct. Indeed, a fourth neurotransmitter system may involve benzodiazepine/GABA.Work in the late 1980s demonstrated that when decerebrate animals that have had their brain-stem transected from the rest of the brain were injected with a benzodiazepine drug (which enhances GABAergic neurotransmission), it enhanced their liking reactions to sweet tastes.

Hence there may be four distinct neurotransmitter systems that mediate the pleasure instinct, each with brain-stem origins.The fact that there could be so many brain-stem locations for inducing different components of the pleasure instinct is interesting and expected since, as we have seen in earlier chapters, these areas are the first brain regions to develop during gestation. Indeed, proper functioning of brain-stem areas is critical, since they control so many fundamental processes that support living organisms (for example, respiration, sleep-wake cycles, feeding, thermal regulation, and so forth). These are ancient brain regions, conserved across all mammalian species. Evolution has built upon their foundation. The central theory espoused in this book is that these brain-stem sites are responsible, in part, for using pleasure to nudge developing humans toward certain stimuli that must be experienced for normal brain development to continue.

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