All right, let’s be honest. The brain is not a lute, and the six brain chemicals we will discuss are not precisely like the six strings of the lute. But the idea I want to explore—that the chemicals of the brain may be likened to specific musical tones—is not without precedent. The ancient Greeks developed the notion that certain musical modes, or scales, possessed “moral values” that could affect the emotional response of the listener. For example, some modes could activate the individual, while others could undermine mental and spiritual balance. (Plato, in “The Republic” and “The Laws,” specifies that only certain kinds of music be played in schools.) While I will not be suggesting such a direct music-to-brain connection—I will not argue, for example, that plucking a specific string of the lute leads to a spritz of serotonin in the brain—I will be presenting a kind of extended metaphor or analogy.
In brief, the brain chemicals underlying mood and behavior relate to one another in roughly the way the strings of a lute interact to produce chords—or, if the instrument is out of tune, discord. Just as one string, when plucked, exerts a harmonic influence on its neighbors, one neurotransmitter in the brain may modify, augment, or counteract another. Just as the lute’s strings may be out of tune, the brain’s chemistry may be out of balance. But there is another, more literal sense in which the chemicals of the brain may be likened to strings. Several of the major neurotransmitters exert their influence by means of rather long nerve pathways, or “fibers,” projecting from one area of the brain to many others. Activating one of these pathways may be likened to plucking a biochemical string. The activating event, of course, is not the musician’s finger, but an electrochemical stimulus. This may arise from something external—seeing a Mack truck bearing down on you, for example—or from an internal event, such as a childhood memory or pleasant thought.
There is another aspect of the brain’s music that we must understand before proceeding. Just as the strings of a lute may be plucked too loudly or too softly, a particular neurotransmitter pathway may be overactive or underactive—spilling out too much or too little of its chemical messenger. This can have disastrous consequences for mental health and stability, as we will see. But the situation in the brain is quite a bit more complex than this. Nerve cells (neurons) in the brain are covered with microscopic binding sites to which a particular neurotransmitter becomes attached. Once a neurotransmitter latches on to one of these receptors, it sets off a chain of events that leads to activation or suppression of nerve-cell activity. Ultimately, the genetic material of the cell may be subtly altered, leading to production of new proteins or hormones. And just as a string may be tuned too sharp or too flat, neuronal receptors may be abnormally sensitive or insensitive. In response to certain stimuli, these receptors may become more or less sensitive or numerous. In short, there are several ways in which the strings of the brain may become louder or softer, sharper or flatter, depending on the amount and effect of various chemical messengers. Finally, like the strings of the lute, each neurotransmitter pathway may affect its neighbors. When one of these chemical pathways is “plucked” over a long period of time—hours or days, let’s say—it may increase or reduce the activity of other pathways. But unlike the vibrations of a string, these neurochemical reverberations often extend over weeks, months, or even years. With our lute analogy in mind, we can now examine some of the principal “strings” of the brain.
Dopamine is the string of fire. Like Prometheus, the Titan who gave fire to mankind, dopamine gives us activation, energy and drive. When the dopamine string is played too softly, we feel lethargic, depressed and “flat.” The chemical system that underlies our sense of pleasure and reward is activated by dopamine. Thus, when dopamine is missing, the Beethoven symphony that once excited us now seems like so much elevator music. The sexual partner who once aroused such passion might as well be the old filing clerk at the IRS. Even our movements are slowed without dopamine. In the case of individuals with Parkinson s disease, a critical lack of dopamine leads to profound deficits in movement and motor function. The “parkinsonian” individual is stooped and shuffling, tremulous and unsteady—the consequence of too little dopamine in a part of the brain called the substantia nigra. In contrast to all this, the individual with an excessively loud dopamine system may be mad or manic. In schizophrenia, for example, we think that excessive dopamine drives hallucinations and delusions. (On the other hand, some of the so-called negative symptoms of schizophrenia—such as apathy and social withdrawal—may be due to too little dopamine in other regions of the brain.) The individual who has just snorted cocaine is deluged with dopamine. Talk about high-strung: The coke addict is euphoric, overly-energized and hypersexual, at least for a few hours. Sometimes, as in schizophrenia, the cocaine user may become grandiose or paranoid. We think that after many years of cocaine use, the addict’s neurons may actually become depleted of dopamine. This withdrawal state can lead to profound depression, lethargy, and somnolence—the infamous “crash” that follows the cocaine binge. Withdrawal, in turn, leads to cocaine craving and further cocaine use, as the addict tries desperately to tune up the slackened dopamine string. A vicious circle of dopamine intoxication and withdrawal often follows. There is some evidence that the manic phase of manic-depressive (bipolar) illness also involves too much noise from the dopamine system; indeed, the manic individual often resembles someone in the midst of cocaine intoxication. Unfortunately, bipolar disorder is driven by its own perverse chords, with bouts of mania and depression alternating over the course of a lifetime.
Serotonin might be called the master string. If dopamine is Promethean, serotonin is surely Protean—after Proteus, the sea-god who could change his shape at will. Serotonin is involved in virtually all aspects of biological function. Sleep, sexuality, aggression, appetite, pain perception, temperature regulation and mood are just a few of serotonin’s domains. If you wanted to buy stock in a neurotransmitter, you could do worse than serotonin. Some of the most widely prescribed medications in the world—Prozac, Zoloft, Paxil and others—are essentially agents for amplifying the serotonin string. (In more technical terms, these antidepressants inhibit the mechanism by which serotonin is taken back up into the nerve cell—resulting in more serotonin to communicate with other neurons.)
What happens when the serotonin string is plucked too softly? Like dopamine, serotonin modulates mood. When its volume is too low, people often get depressed. By increasing the amount of serotonin between brain cells, Prozac-type medications can alleviate many cases of depression. (For that matter, so can psychotherapy—and there is every reason to believe that “talk therapy” can affect the chemistry of the brain just as medications can.) More surprising, though, is the connection between low serotonin and aggression. People who tend to be impulsive, violent, or self-destructive seem to have too little serotonin in their central nervous systems—or their serotonin receptors are somehow “tone-deaf” to the neurochemical signal sent out by serotonin neurons. Over the course of many years, these receptors may try to compensate for this weak serotonin signal by becoming more numerous or more sensitive—a process sometimes called up-regulation. Paradoxically, what started out as a serotonin deficiency can gradually become a serotonin surplus. Some individuals who wind up with too much serotonin are prone to develop various kinds of anxiety disorders, such as obsessive-compulsive or panic disorder.
Scientists have found that, in such cases, drugs that “tone down” or antagonize serotonin receptors may work as anti-anxiety agents. Oddly enough, Prozac-type medications may also be useful. It may be that by pumping up the volume in the serotonin system, hypersensitive serotonin receptors are gradually able to “down-regulate” back to their original state. All this is just to say that the chemistry of mood is complex and tightly regulated. When the serotonin string is either too soft or too loud, too flat or too sharp, mood and behavior may suffer.
Sleep, appetite and pain are also modulated by serotonin. For example, the serotonin string is quite loud during waking arousal, and virtually silent during a type of sleep called REM (for “rapid eye movement”). During REM sleep, which is closely linked with dreaming, the individual’s muscle tone is normally very low—probably due to serotonin’s silence. This is fortunate, since without suppression of muscle tone, someone dreaming of, say, punching out the boss might act this out upon an innocent bed-partner. (Indeed, in REM sleep behavioral disorder, some people manifest just such violent activity.) Many people who took the now defunct “fen-phen” diet pill may not have realized that serotonin was fundamentally involved in this double agent’s action. The “fen” part of the pill was the drug fenfluramine, which boosts serotonin levels in the nervous system. The “phen” part was phenteramine, which is an amphetamine-like stimulant intended to offset fatigue induced by fenfluramine. The good news is that by amplifying the serotonin string, fenfluramine suppresses appetite, and hence, promotes weight loss. The bad news is—as the Food and Drug Administration belatedly realized—that the fen-phen combination seems to cause damage to the valves of the heart. Thus, this agent was removed from the market. Nevertheless, researchers are still interested in the ways in which serotonin may influence appetite and weight. Finally—though the serotonin story could go on for volumes—we know that pain perception is greatly influenced by the serotonin system. For example, people with chronic pain syndromes often benefit from agents that amplify the serotonin signal.
Serotonin does not act independently of other neurotransmitters, of course. When its string sounds, it actually dampens the reverberations of dopamine. This may be part of a subtle homeostatic system in the brain, designed to keep mood and motor activity in careful balance. Unfortunately, it can sometimes lead to unwanted medication side effects, such as the parkinsonian symptoms occasionally seen with Prozac-type antidepressants.
Many of us remember the “fight-or-flight” response from high school biology. That Mack truck we mentioned earlier—bearing down on us at 70 miles per hour—evokes a chain of events that equips us either to escape from danger or to confront it head on. We begin to feel our hearts pounding and our breathing increasing in rate and depth. Blood rushes to the muscles of movement, and we are transformed into lean, mean, fighting—or fleeing—machines. One of the chemicals responsible for this fight-or-flight response—adrenaline, or epinephrine—is produced by the adrenal gland. A close cousin of epinephrine called norepinephrine is an important neurotransmitter in the brain. As you might guess, norepinephrine tends to be an activating chemical. When its string is plucked, you know it. In fact, excessive norepinephrine in a part of the brain called the locus ceruleus may underlie the phenomenon of “panic attacks”—an instance of the fight-or-flight response gone haywire. Some symptoms of mania and post-traumatic stress disorder may also be related to too much noise from the norepinephrine system. On the other hand, when the norepinephrine string is muted or flat, depression may ensue. There is some evidence, for example, that depressed patients have less sensitive norepinephrine receptors than do non-depressed control subjects. (These studies have actually been done on white blood cells, not brain cells, in depressed subjects; however, the receptors are very similar in both types of cells.) It is interesting that after treatment with electro convulsive therapy (ECT), these norepinephrine receptors achieve normal sensitivity. Since ECT is the most effective treatment known for severe depression, this finding provides evidence that the norepinephrine string may be “flat” in some depressed patients.
GABA, Glutamate, Acetylcholine
Most of the medications that act on mood affect one or more of the three “strings” we have just discussed—dopamine, serotonin, or norepinephrine. However, there are probably scores, if not hundreds, of other neurotransmitters in the human nervous system, each contributing a unique tone to the symphony of mood and behavior. There are three more strings we must discuss here, but these could easily be replaced with others of different tone and timbre.
Two neurotransmitters—GABA and glutamate—remind us of those two contrasting gods in Greek mythology, Apollo and Dionysus. Apollo is usually described as the god of order, light and reason. Dionysus—related to Bacchus, the Roman god of wine—is linked with turbulence, darkness and sensuality. And yet, as Nietzsche taught us in “The Birth of Tragedy,” it is the creative tension between the Apollonian and Dionysian that generates the greatest art and drama. In the brain, GABA and glutamate represent opposing neurochemical principles; and yet, their coordinated activity regulates the energy level of virtually every neuron in the brain. GABA—short for gamma aminobutyric acid—is the main inhibitory neurotransmitter in the nervous system. Unlike our previous neuro transmitters (called biogenic amines), GABA is an amino acid—a building block of proteins. GABA is ubiquitous in the human central nervous system, with as many as a third of all neurons utilizing GABA as their primary neurotransmitter. If we say that our first three neurotransmitters “fire up” the neuron, we might justifiably say that GABA puts the fire out. When GABA latches on to its receptor site, it causes a flood of negatively charged ions to rush into the neuron, dampening the cell’s electrical activity. Repeated over many thousands of neurons, this process seems to underlie behavioral sedation or calmness. When the GABA string sounds, its tone is likely to soothe “the savage breast.” Indeed, sedative-hypnotics like Valium and Xanax depend on the activity of GABA for their mechanism of action. When too loud or too insistent, the GABA string may bring on stupor or even coma.
In marked contrast, glutamate is the primary excitatory neurotransmitter in the brain. Glutamate’s string sends bold reverberations throughout the brain, awakening the very cells that GABA would put to sleep. Like Dionysus, who could bring madness to those who rejected his divinity, glutamate can bring destruction to the brain, if its activity is too great. Through such excess, neurons can literally be “excited to death.” Some data suggest that such “excitotoxicity” underlies the damage seen in stroke and Alzheimer’s disease. Ironically—or perhaps quite sensibly in nature’s clever economy—glutamate is actually the precursor of GABA. It seems that when neuronal activity gets too intense, the enzyme that converts glutamate to GABA is activated—suggesting that the fine counterpoint between these two contrasting strings provides the brain with a self-regulating calming mechanism. (It is tempting to speculate that in some extraordinarily anxious persons, this enzyme system is somehow defective.)
Finally, our sixth string—acetylcholine. Outside the central nervous system, this neurotransmitter is involved in muscle contraction. (Curare, the poison that brings on muscle paralysis, works by interfering with acetylcholine.) In the brain, acetylcholine is closely involved in memory and higher cognitive functions. When its string is plucked, we can count, calculate and generally sound clever. Individuals with Alzheimer’s disease have very low levels of acetylcholine in their brains and, as a consequence, have great difficulty with memory and cognition. Acetylcholine also affects mood. Too loud a tone from this string, and the individual may feel depressed; too soft, and the person may veer toward euphoria or mania. (So-called anticholinergic agents—which interfere with acetylcholine—are actually sold on the streets for their mood-elevating “buzz.”) A number of medications for Alzheimer’s disease have the effect of restoring brain levels of acetylcholine back to normal.
Chord and Discord in the Music of the Brain
So how do things sound when all six of our strings are played together? How do the chemicals of the brain create the equivalent of chords? What combination of tones leads to discord in brain and behavior? We are a long way from knowing the answers to these questions, but we can make some generalizations. First, it is clear that certain mental illnesses are critically related to abnormalities in one or more of these six neurotransmitters. For example, in schizophrenia, the dopamine string may be too loud in some regions of the brain, while the GABA string may be too soft. This has very direct implications for our treatment of schizophrenia, which normally utilizes drugs that block the dopamine receptor. (Drugs that increase GABA usually have a modest, adjunctive role in treatment.) It is also clear that simple “deficit” theories of mental illness do not do justice to the abnormal brain’s cacophony. For example, depression is unlikely to involve simply too little serotonin or norepinephrine. Rather, the amounts of a neurotransmitter, the sensitivity of its receptors, its effects on the gene, and its interactions with many other neurotransmitters may all determine its effects on mood. In the larger arena of temperament or character, we have reason to believe that traits such as shyness or risk-taking may be related to the state of one’s neurochemical strings. For example, socially phobic individuals may be deficient in serotonin, while “risk-takers” may have a bit too much dopamine on the brain. (At present, these associations are very tenuous.) Finally, knowing more about the music of the brain may lead us toward ways of enhancing mood, memory and behavior. While human creativity can never be reduced to mere neurotransmitters, we may be able to modulate that creativity by tuning one or more of our strings up or down. Perhaps we can even envision a whole new instrument in which not six, but a hundred strings will play in symphony.