Richard M. Restak, M.D.

RECEPTORS

Chapter 1:  DISORDERED THOUGHT, DISORDERED MOLECULE

At a Fourth of July party I recently attended, the hostess proposed a game. She provided all her guests with name tags and affixed them to each of their foreheads, but in place of their own names she had put the name of a historical person, place, or event. People could read the names on the others' brews but couldn't see and therefore didn't know their own. The object of the game was for each person to discover his or her identity by asking questions of the other guests.           

That night I had a dream in which I was at a similar gathering, but the guests and theme of this dream party were different. All the world's most distinguished brain scientists were there, and affixed to their foreheads were the names of parts of the brain. Some of the labels referred to large brain areas such as the temporal lobe or to microscopic nerve cells like the neuron; others identified chemical messengers-neurotransmitters-within the brain; still others identified processes like synaptic transmission, whereby a chemical message is transferred across the synapse, the tiny space that separates nerve cells. Since I have been studying the brain all of my adult life, none of this seemed surprising to me: not the setting, nor the participants, nor the game itself.            

In my dream I am talking to a neuroscientist who has the neurotransmitter dopamine written on her brow. Thanks to her clever questioning, she has already discovered her own identity and is trying to help me discover mine. But whatever I ask her, no matter how skillfully she answers, I cannot seem to guess what is written on my forehead. Finally, the woman reaches out, puts her arms around me, and plants a lovely kiss on my lips. She then steps back, her eyes wide open, and asks, "Do you know now?" And of course, I do. I am the receptor for dopamine. Like two lovers, dopamine and its receptor, like all brain neurotransmitters and their receptors, embrace across the synaptic junction.      

  My dream intrigues me for a couple of reasons. One is the Fellini-like situation of brain scientists using their own brains in order to guess the name of the brain element they have been assigned to represent. Further, all the participants in this fantastic dream situation, when taken together so that they include all of the various brain parts and processes, represent the brain in its entirety. Moreover, on the basis of their assignment of a single brain element each, the players are being challenged to comprehend not only their individual identity and their participation in the brain's operation but the operation of the brain as a whole. In essence, parts of the brain are being challenged to understand the functioning of the whole.           

Is this possible? Can the study of one component--say, the most elemental unit, the neuron--provide insights into the functioning of the whole? On the heels of that consideration comes the image of my seductive interrogator, the brain messenger reaching out and embracing the specific receptor--in this exciting dream, me. A neuron sends a message to another neuron by releasing a neurotransmitter across the synapse to a receptor site on the membrane of the target neuron. That receptor is specialized to receive that neurotransmitter. This is how nerve cells of the brain communicate, both within the brain itself and outside it, with the entire body. What part does this intricate neurotransmitter-receptor interaction play in the operations of the brain?    In this book, I propose that our understanding of these operations is being remarkably advanced by what we are learning about the relationship of the brain messengers to their receptors. This burgeoning understanding has far more than theoretical importance. In the next decade receptor research promises to bring about remarkable, wide-ranging advances in our understanding of human behavior and in treatments for thus-far-incurable mental illnesses and for drug addiction. The application of these advances extends beyond understanding extraordinary mental states. It also holds promise of improving normal functions: enriching memory, enhancing intelligence, heightening concentration, and altering for the good people's internal moods.            

Throughout history, insights into how the brain works have been shaped by the technology and the scientific biases of a particular time. The early Greeks, influenced by the technology of aqueducts, thought of mental processes in terms of the flow of bodily fluids. In the seventeenth century the philosopher Descartes compared brain functions to the operations of machines. The nineteenth century emphasized anatomy, the physical connections of one brain part to another. This view of the brain was stimulated by widespread fascination with railway lines and the demonstration that communication depends upon physical connectivity over distance. A similar connectionist view was espoused in the early years of the twentieth century by a famous brain scientist, Sir Charles Sherrington, who compared brain operation to a telephone switchboard. Today brain function is often compared to circuits and computations, reflecting the influence of electronics and computers in our age. But none of these technological metaphors ever hit the mark with sufficient precision to withstand the assault of the next innovation. Analogies to other processes and "machines," no matter how sophisticated, falter when placed against the complexity and uniqueness of the human brain.

     If the brain is not like an aqueduct or a railroad or a telephone switchboard or a computer, and if future technological metaphors are just as likely to be displaced, what then is the best way of thinking about it?

    Over the past quarter-century, and especially the last ten years, a new way of thinking about the brain and the mind--functionally defined as operations carried out by the brain--has flourished. Rather than emphasizing anatomy, which is essentially another mechanical theory of how the brain works, this new theory concentrates on understanding the brain on the chemical and molecular level. Since this can be a somewhat difficult point to grasp, at least initially, an incident that occurred during my residency may help illuminate it.

     In my training years in neurology I worked under a morose, short-tempered teacher who was far more interested in the chemistry of mental and neurological illnesses than in the care of patients afflicted with these illnesses. He was not an uncaring man; rather, he had become so immersed in his research that what he could see or hear or touch failed to stir within him the passion that the invisible molecular world inspired in him. 

    One afternoon I walked into his lab unannounced to ask for his help in managing a patient I had just seen. I was just starting my residency training, and I was often uncertain about how to proceed with the patients who sought care in this big-city emergency room.

            As I spoke, my chief listened to what I was telling him, but he continued to stare down at the chemical formulas on the papers spread out before him. At the conclusion of my presentation, he gave me an incisive, accurate diagnosis, and even more welcome to my ears, he told me what to do to help my patient.

            Then as I was turning to leave, he said something that has taken me twenty years to understand: "Now, please go away and tend to that macromolecule in the emergency room, and leave me here to deal with these micromolecules."

Over the next several days we neurology residents would break into bursts of laughter whenever we thought about his strange remark, this weird idea of a living, breathing human being as a "macromolecule" that could be compared to or equated with molecules in the brain. Two decades later, my teacher's comment seems much less bizarre. Research on the human brain suggests that we share certain properties and reactions-with the micromolecules of which we are constituted. Perhaps the one who has come closest to understanding this continuum from the very small to the very large was the man who suggested, "Behind every crooked thought there is a crooked molecule." In short, all things mental--both normal functions and disorders of thought and emotion--originate from some corresponding order or disorder at the molecular level. Over untold millennia nature has evolved certain principles and, since they work, employs them again and again at various levels of the organism. Further-and this is the theme that we will be developing in this book--nature displays a marvelous parsimony, in which events at one level mirror what is going on several higher or lower orders away.

The common unit at all levels is information. Information can take the form of the words on a page, or the signal that instantaneously moves a finger away from a hot surface, or the swirl of neurotransmitters within a synapse between neurons. Indeed, as Umberto Eco pointed out in a conversation several years ago, the whole world and everything in it, including the brains of everyone in the world, can be thought of in terms of information. There is information in the shape of a leaf, in the sound of a sparrow, in the molecular structure of water, and in the multitude of chemicals that make up our bodies. Over the eons the human brain has evolved to encode and decode myriad forms of information. It does this through neurotransmitters, each of which has its own chemical formula but shares a common purpose with the others: to communicate information from one brain cell to another.

The recognition that communication at the molecular level may be at the root of brain functioning had its impetus in the field that is now called neuropsychiatry: a science rooted in the belief that mental illness and emotional disturbances can be understood and treated in terms of disturbances in the functioning of the brain.

Neuropsychiatry is a comparatively new field, although mental illness is as ancient as human history. Only fifty years ago, theories about the origin and management of mental illness still depended upon unproved and essentially improvable assumptions about human behavior. Although psychoanalysis and other "talking" therapies had their place in the treatment of neuroses and milder forms of mental illness, they were generally far less useful in treating psychoses. The number of people confined to mental hospitals in the late 1940s was at an all-time high, most of them suffering from major psychotic disturbances, but for the most part psychiatrists operated outside the "medical model" in treating them. The prevalent treatment methods consisted of efforts to control a patient's disturbed behavior-restraints, cold packs, isolation cells--and the most pervasive of all, neglect. The only drugs then available had a similar purpose: control. But they were unreliable and often dangerous. Barbiturates brought about some calming of agitated patients, but at the risk of oversedation and dependence. Bromides enjoyed some popularity for a time, but they often induced their own form of madness, known as bromidism. Biological treatments, also called somatic treatments, were limited to electric shock and insulin coma therapy. Not only did they fail to bring about reliable and repeatable improvements in patients, they were also frightening and were perceived as dangerous and repugnant. Insulin coma therapy deliberately reduced a patient's blood sugar until coma set in; the risks included brain damage and death. Electric shock treatment, also called electroconvulsive therapy or ECT (which is used today with far greater safety and  effectiveness), was often applied inappropriately and without adequate precautions to protect patients from injury. 

Though trained as physicians, most psychiatrists of the time had little interest in neurology, the science of the brain and the nervous system. By current standards that may sound like a serious indictment, but it is not meant to be. This was still an era in which mental illness was generally perceived--by almost all doctors, not only by psychiatrists--as resulting from disturbances in the mind, as distinct from the body. Psychiatrists actually had more in common with psychologists, philosophers, and others who looked upon human personality in ways that excluded biology, than they did with other physicians. 

There were, however, a small number of psychiatrists who recognized the significance of the brain in mental dysfunction. Some had been formally trained in the brain sciences-neuropsychiatrists who shifted their professional interests from neurology to psychiatry. (This was the path Freud had taken many years be- fore.) But most lacked professional training in neurology, and had only a gut feeling that the mind could not be properly understood without reference to the brain and nervous system. They had no way of proving this, however. 

Today, all that is changed. Our understanding of the brain and central nervous system has taken a quantum leap, and with it has come the development of mind-altering drugs that literally act on the "crooked"-disordered-molecules that have been found to characterize many mental disorders. Today we know that our thoughts and emotions, both normal and disturbed, are the result of chemical processes going on within the brain. Alter these processes, and the thoughts and emotions will be altered. The new drugs that change the chemistry of the brain make clear that we can change our internal states deliberately. 

Chemical alteration of the brain is not something new in history; human beings have done it for millennia. But our increasing understanding of the processes involved is very new. For thousands of years people have sought altered states of conscious ness by distilling mind-altering ingredients from plants. Some of these are exotic, but many are so commonplace that we do not even think of them as drugs. Few people complete a day without recourse to a stimulant--coffee or tea or chocolate. Is there any- one who has never taken an aspirin for a headache.  When we want to relax, some of us reach for a drink or a cigarette. These are all brain- and mind-altering substances, and since they are all legal, there has usually been no shame or guilt or embarrassment about using most of them. 

That has recently changed in some respects. It is much harder now than it was five years ago to light up a cigarette at a cocktail party without being challenged on the dangers of passive smoking. Overall, the consumption of alcohol too is down, particularly the hard liquors that were once so popular. Part of the reason for these changes in attitude stems from our increasingly sophisticated knowledge about addiction. We now recognize alcohol and tobacco as substances capable of rendering us unable to live without them. 

At a different level of urgency is our recognition of the consequences of widespread cocaine, heroin, and marijuana use. We see these consequences around us everywhere: deaths from drug overdoses, the murders of drug dealers by one another, the growing violence among the young, the dangers epidemic in our cities. Drugs are frequently associated with automobile accidents, ship- wrecks, plane crashes, and train disasters; people today commonly embark on a journey on any form of transportation with a gnawing fear that the operator might be on drugs. Drug addiction and the apparently intractable problem of what can be done about it are a constant presence in our lives. 

One thing is certain: Blanket prohibition of mind-altering substances won't work; nor will efforts to differentiate between “good,” and "bad" drugs, for reasons we will explore in Chapter 10. Brain and mind alteration through chemistry is a fact of our lives. Illicit drugs apart, try to imagine what our world would be like if suddenly, overnight, all pain-killers, sedatives, caffeine- containing compounds, nicotine, and everything containing alcohol; all tranquilizers, antidepressants, and anticonvulsants were simply to disappear. Is there anyone so harsh and puritanical among us that he or she would deny pain relief to cancer patients, or to those suffering the chronic pain of arthritis or migraines2 Who would refuse to relieve, if not "cure,)' mental patients of their delusions and anguish with appropriate tranquilizers2 Do not tea and coffee, when taken in sensible amounts, make life more pleasurable~ And would we really be happy in a world with- out chocolate? Although some of us might prefer a world without alcohol  a world that has never existed, even in earliest times-- the vast majority would not like to do away with this mind-altering substance altogether. Rather than eliminate all these substances-- an impossibility--we would like to know how to control them better. In order to do this we must understand how they affect our brains. 

All such substances, licit and illicit, therapeutic and common- place, natural and synthesized, provide windows into the functioning of the brain. What is now emerging from the laboratories of molecular biologists and psychopharmacologists are new brain- and mind-altering drugs that have an even vaster potential to alter how we feel and act. To understand these explosive developments, let us turn to the organ upon which these substances act, especially those areas that play important roles in emotions and behavior. 

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