THE SMALL BAND of hunter-gatherers had been traversing the savannah for days, making good headway in the low morning light, resting in a patch of high grass through the hottest midday hours, and then moving on again, until the fall of darkness. A few days before, waving sticks and throwing stones, they had been able to chase off two hyenas and scavenge what remained of several antelope carcasses, left behind by some unknown predator. They had stayed at the site and feasted until no one could eat any more, and then used sharp stone tools to cut off the meat for drying and preserving. But for days now they had not been able to find water. At dusk the men sat and whispered while the women attended to the more and more lethargic children. The stream the band used to move toward during the dry season was nowhere to be found. In the end they had made their decision. The word traveled around the group, and once all the adults had nodded, the band started moving down the slope, toward the valley and the lake below.
The day turned to night, but this time they pressed on, some of them anxiously looking over their shoulders, others just quiet and determined. Hours later they saw the first moonlight reflected off the water. They pressed on until they reached the edge of the thick bush that bordered the last clearing separating them from the lake. They hunkered down at the edge of the bush, looking out for dangers in the night, pulled by opposing forces. The cool water lay before them. Looking down the gentle slope of the clearing, the thirsty travelers could almost feel a soothing, satisfying sensation on their cracked lips and dry tongues. But another force pulled them back. There was danger there, too. The men whispered to one another again. More than one of them had seen glittering eyes in the darkness or heard the sounds of struggle on a night like this, just before a member of the band was lost to an unseen hunter.
Some of the younger men were ready to take on any dangers. Others stayed still, as if frozen. In the end a scarred male who always seemed firmly planted in the ground raised his hand and spoke. It was true, he said, they had to have water. But leaving the bush and traversing the clearing at night was just too dangerous. They would wait until daylight, when the predators could be counted on to doze off in a lazy slumber. Only then would the band make its move. Some of the band members tried to object. One of the women pointed to her dry breasts and the baby she had put down on the ground, barely breathing now, with shallow, short breaths that almost didn’t lift its chest. But the others knew the scarred man was right. They waited, biding their time, some drifting off into an uneasy slumber, others patiently staying awake, watching the stars move across the firmament. The baby gave up its last breath sometime before sunrise. Its mother cried quietly, rocking the little body back and forth while it lost its warmth in the cool predawn hour. Then, finally, heralded by a glorious aura, the ball of fire broke through the horizon, and sharp shadows started moving across the ground once again, marking the beginning of yet another day.
The band silently broke away from the bush and made their way down to the waterline. Once there, all but one of them laid face down, eagerly gulping down the clear lake water. The scarred man was the only one to wait just a bit longer, continuing to watch for dangers that might linger along the lakeside. Finally he too was convinced they were safe, at least for now. The baby had died, but the band had survived. And new babies would soon be born.
The complexity of the human brain is quite intimidating, even to those of us who have devoted our lives to exploring it. The estimated number of nerve cells, or neurons, in an adult brain was recently revised down but still stands at a mind-boggling eighty-five billion. Each of these cells has perhaps ten thousand connections, or synapses, that connect it to other neurons. Using different messengers, or transmitters, with an intensity that varies from millisecond to millisecond, these connections transmit information that is coded for most of its travel in much the same way as an FM radio transmitter codes its signal.
1 Over a longer period of time, the connections change in strength, based on prior experience and activity level. When the sparking of cells starts, a neuron comes together with others in a transiently formed ensemble that creates the brain’s inner representation of a particular stimulus, a response, or some more abstract process that happens between those two. But the next moment, the same neuron will begin a dance with an entirely new set of partners, to represent something else. For now the question whether the workings of this machinery are in principle deterministic is hypothetical. Understanding what is going on and predicting how this complex machinery will respond to interventions are both challenges.
Scientists who try to understand the brain mechanisms of addiction take different approaches to these challenges. Some choose to study a model system that represents a tiny part of the big problem, but one that in return can be understood almost perfectly. For instance, some of the most advanced neuroscience research today applies a Nobel Prize–winning technique
2 to slices of a mouse or rat brain. While nerve cells in the slice are kept alive, minuscule electrodes allow the scientists to exactly measure the way communication between cells takes place. This kind of system allowed scientists to establish that exposure of the rat brain to a single dose of cocaine can change the strength of critical synaptic connections within what I soon will introduce as the “brain reward system,” through a mechanism similar to that seen in memory formation.
3 Other investigators focus on problems at the other end of the spectrum. Studying the complex behaviors that the brain produces, they have, for instance, found that exposing cocaine or alcohol addicts to psychological stress makes them crave, and that the level of craving elicited in this manner predicts much of the risk for subsequent relapse.
4 Clearly the processes most obviously relevant for the clinical problems of addiction are also the most complex and hardest to measure in an objective and reliable manner. The most basic and well-defined experiments are, on the other hand, somewhat removed from the clinical problems of addiction. There is a whole world of intermediate levels in between.
It is not easy to know how to handle this dilemma. We hope that science will one day be able to connect these different levels of complexity, and that scientists will work on all of them. But for now the connections are just not there. Knowing that synaptic strength in a particular brain circuit changed because the patient took cocaine does not at present help me figure out how to manage cocaine addiction in the clinic. Until we have a more integrated understanding of how basic processes and complex behaviors are linked, we need to find a pragmatic level of simplification. On one hand, this simplified view should come close enough to the phenomena of drug seeking and relapse to help us make clinically useful predictions—for example, “If a medication can be found that will reduce the patient’s reactivity to psychological stress by a certain amount, then that patient’s risk of relapse over a certain period will be measurably reduced.” On the other hand, this simplified view needs to be firmly grounded in what we currently know about basic molecular and cellular processes of the brain. It is not immediately obvious where this just-right amount of simplification lies. And we can hardly let this be decided by media reports of the latest hot story, which almost always are oversimplified, with a focus on the transmitter or gene du jour.
Useful guidance can, however, be obtained from a somewhat surprising source. A famous statement, put forward in a very different context, asserts: “Nothing in biology makes sense except in the light of evolution.”
5 Immersed in the fast-paced, high-tech twenty-first-century world, it is easy to forget that our brains have been shaped by fundamental conditions of human existence that have remained unchanged in the hundred thousand or so years since we left our ancestral homes in Africa. Many of these fundamentals are captured in the brief episode from the history of our species recounted at the beginning of this chapter. As we are born, live, and die, our children and their children represent the only hope we have that life will continue, and so traits that help propagate the species evolve and become enriched in the population. While we live our individual lives, a peculiar excitement pulls us toward things desired, be they food, drink, or a prospective mate, or energizes the exploration of a novel place, where some of those desirable things might be found. Once the object of desire is reached, there is often—although certainly not always—pleasure.
But in a world full of dangers, unease, aversions, or outright fear constantly lurk as equally powerful forces, trying to steer us away from threats that otherwise might bring an end to the pursuit of our desires. There are, of course, many different kinds of fears and aversions, some of which we are born with. Faces, the most important communication device of our species at least until the smart phone was invented, are, for instance, detected by built-in brain hardware that needs only a few face-like features to flag them. And fearful faces, a sure sign that our peers have detected danger, reliably trigger fear responses in those who see them, without any learning being required. Other fears are learned. Perceptions that were once of little interest can become powerful triggers of fear if in the past they have been followed by distress. A third category, curiously enough, falls between the innate and learned fears: we are born with a preparedness to learn to fear them. It is, for instance, much easier to acquire a fear response to a snake-like object than to a rose-like one. Whether innate or learned, most of this happens quickly and beneath the level of consciousness. All of it is, of course, in the service of survival, without which no rewards are particularly meaningful. And beyond the acute fears there are other aversions, equally important for survival. In a pre-antibiotic era, disgust triggered by the smell of spoiled food was clearly a great help in avoiding death from food poisoning.
As the forces of reward seeking, on one hand, and fear and aversion, on the other, play tug-of-war within a person, a third category of processes arbitrates. Reason, much of which is concerned with planning for the future, helps the person trade off the rapid satisfaction that might come from pursuing desires against the need to avoid dangers. It also helps find a trade-off between the pursuit of immediate happiness, on one hand, and the achievement of greater but longer-term gains, on the other. For this, a whole set of new or improved tools are needed that are uniquely human; dogs don’t have them, and chimps possess them only in a limited degree. For starters, there is a need for systems that can represent future, hypothetical states, a concept brilliantly captured in the famous expression “memory of the future.”
6 Of course, multiple such “memories” need to be represented as possible alternatives, so perhaps “memory of multiple hypothetical futures” is a better, if less elegant, expression. Systems are then needed to assign values to these outcomes, also taking into account how far into the future they lie. Who knows? Putting off that dream vacation in order to purchase bonds that do not mature until a hundred years from now really does not make sense. The chances that I will still be around that far into the future are not very encouraging. But twenty-five years? Who knows? Choices, then, need to be made between the value-assigned outcomes, and these choices need to guide behavior, often by first suppressing what is going on already, and mustering the energy to switch gears.
In the end, it is the interplay of these forces and then some that allows humans to navigate the world in a way that is very different from that of all other species. The circuitries involved have different histories; some are ancient, others more recent. This history has shaped the relationship among the different processes, and their respective strength in modulating other circuits. It is also this history that suggests which behaviors might make sense to study in the laboratory using lower species such as mice and rats, and which may be sufficiently different in humans to make such studies difficult. And so a perspective on human behavior from the vantage point of our history as a species and the evolution of the brain is useful in learning how brain circuitry produces feelings, decisions, and behaviors that are at play every day of our lives. Yet it is that same circuitry and the same processes that make an addicted patient engage in the seemingly incomprehensible behaviors of addiction.
To put it bluntly, how can behaviors produced by brain circuitry that evolved to promote survival instead kill you?
It was late night, and I was getting frustrated. Months before, I had applied for a job I wasn’t sure I really wanted—one that would mean a 50-mile commute each way and add to my already unbearable administrative duties. By now we had as a family decided we were instead moving back to Sweden, and I had just returned from a quick trip to finalize the details of the coming move. Funding was agreed on, space was selected, and the university had helped me get our girls signed up for a school that seemed quite good. After a night back home, I had packed a smaller suitcase and flown on to a conference in St. Louis when the phone call reached me: would I still like to give a job talk? Now I was back home once more, in my basement office, preparing for that talk. I sighed. At least this was an opportunity to do something scientists too rarely get to do, because we are constantly so busy generating data and writing empirical papers: sit back, read, and think.
The immediate problem was very specific. For the talk I could pick one or two particularly exciting datasets and use those to share my enthusiasm, point to research strategies I think hold promise in our field, and illustrate my vision for how science can address important problems of addiction. That kind of approach would be fun—there are few things I love more than real data. But it would necessarily leave out everything else. If I spent time talking about how genetics makes different people get different rewards from alcohol, people would likely think I subscribe to the view that rewarding properties of addictive drugs are what matters most for addiction. That leaves out a whole theme of how stress and negative emotions drive drug seeking, which I think is crucial, and to which I have devoted most of my own research efforts for many years. If instead I showed data on how antistress medications reduce drug seeking and taking, I would likely create the opposite impression. Showing a bit of each, I would have the worst talk possible: seemingly random fragments, joined by the arbitrary fact that they happened to be generated in my lab. Clearly I needed a framework within which to present selected data—a framework that would work for a one-hour talk to a diverse audience yet avoid offending some of the world leaders in addiction research who would also be listening.
I decided this was a time to try to convey my big-picture view of brains, behavior, and addictive drugs. Inspired, among other things, by a beautiful review article that was on my desk at the time,
7 I decided to fit the data I wanted to show into the three domains outlined above, represented by color-coded spheres. These spheres would represent the basic systems that execute brain functions I thought to be most important for addictive behaviors, and that could also be targeted for treatment, be it behavioral or pharmacological.
I needed to make three things clear: First, each of these systems can in turn obviously be broken down into ever more detailed subsystems, eventually all the way down to the individual synapse. Second, the boundaries of the main systems were to some extent arbitrarily drawn, so that parts of them could sometimes be viewed as participating in one or the other, depending perhaps on the circumstances. Third, a myriad of other processes were also important and not easy to fit into the three main systems but nevertheless relevant for what happens in addiction. Yet the three-sphere approach to brain circuits, behavior, and addiction actually turns out to be quite useful. And it does make perfect sense in the light of evolution.