15.1: Neurons

Neurons have surfaces that bristle with finely branched antennae called dendrites (meaning of a tree in Greek) (Figure 15.1). Dendrites receive nerve impulses.

Figure 15.1: The Neuron

A neuron has a long extension called an axon (meaning axis in Greek), which branches at the end and relays impulses to other neurons or tissues. The length of an axon varies from hundredths of an inch to much longer—the axon of a neuron connecting the spinal cord to the toes is more than three feet long in a tall person.

Most axons are wrapped in myelin, a white substance made of fat and protein. Myelin insulates the transmission of nerve impulses, much like insulation around electrical wires. Myelin continues to form around axons during the first year of life. Infants become more coordinated and respond faster to stimuli as this process is completed.

In multiple sclerosis, there’s patchy destruction of myelin, resulting in various neurological symptoms, depending on where and how bad the damage is. The cause isn’t known, but it’s an autoimmune disease—the immune system sees parts of the myelin as foreign and destroys it. Its effects are like the shorting of an electrical system when insulation around the wires is damaged.

Neurons seem to stop dividing after early infancy, in which case they can’t be replaced when lost (the use of stem cells for regeneration is being studied). But other neurons can help compensate. When a stroke causes loss of speech, speech often can be relearned by training other neurons.

Transmission of Nerve Impulses

A nerve impulse is transmitted along the cell membrane of a neuron. The membrane is polarized: Its outer surface is positively charged and its inner surface negatively charged (Figure 15.2).* When the neuron is stimulated, positively charged sodium ions enter, reversing the polarity of the cell membrane at this spot. The impulse (“wave” of depolarization) travels down the axon, much as a “wave” in a rope travels down the rope when it’s snapped at one end (Figure 15.2).†

Figure 15.2: Transmission of a Nerve Impulse

Sodium ions enter through a membrane protein (Chap. 9) called a sodium channel. Some toxins can block it. For example, parts of puffer fish (fugu) have a potent poison that blocks the channel. Eating fugu sashimi (the raw, delicate slices of this fish—a gourmet dish in Japan), is said to give “a pleasant tingling sensation” in the mouth. Too much of the poison leads to respiratory paralysis, a rather unpleasant inability to breathe. How well the chef keeps the poison from contaminating the sashimi can be a matter of life or death to the gourmet.

^{*Fluid around the neuron has an excess of positively charged ions (Chap. 3); the fluid inside has an excess of negatively charged ions. Ion channels (membrane proteins) in the cell membrane control the transport of ions in and out of neurons. Bert Sakmann and Erwin Neher won a 1991 Nobel Prize for developing a method of studying ion channels in living cells.
†For their discoveries of how impulses are transmitted in neurons, Alan Hodgkin and Andrew Huxley shared a Nobel Prize in 1963.}

Neurotransmitters

A nerve impulse is transmitted from one neuron to another. But neurons aren’t physically connected. The gap between the transmitting end of a neuron and the receiving end of another is bridged by chemicals called neurotransmitters. This gap (and its chemical connection) is called a synapse (Figure 15.3), meaning to fasten together in Greek.

Figure 15.3: Synapse Between Neurons

Neurotransmitters are made in the neuron and stored at the end of the axon (the transmitting end; Figure 15.3, 15-4). When a nerve impulse reaches the end of the axon, the neurotransmitter is released and attaches to receptors on the adjacent neuron. This allows the impulse to resume its course. After the neurotransmitter does its job, it’s removed from the receptor so that the cell can return to a resting state.

There are many kinds of neurotransmitters. Some of them have other functions, e.g., some are amino acids. They add another complex dimension to the nervous system. Different neurotransmitters have different actions; the amounts released vary; they can be removed at different speeds; and other chemicals can enhance or hamper their action.

Drugs used to treat anxiety and mental illnesses (e.g., tranquilizers), “recreational” drugs (e.g., cocaine), and even the drug in our coffee (caffeine) act at these synapses. Antidepressants Prozac and Zoloft hamper the removal of the neurotransmitter serotonin.

Neurotransmitters also can affect the sensitivity of neurons. Neurotransmitters and drugs that stimulate neurons (or make them more sensitive to stimulation) are called, yes, stimulants. Those that make neurons less sensitive are called inhibitors. Stimulants lessen the polarization of the cell membrane (Figure 15.2), making it easier to initiate a nerve impulse. Inhibitors enhance the polarization, making it harder to depolarize.

Neurons can have a thousand extensions with which to receive and transmit impulse (in the human forebrain, there are tens of thousands synapses per neuron). So whether a neuron is stimulated enough to transmit an impulse depends on the net effect of the stimulation and inhibition occurring at its many synapses.

When we consider the subtlety of our mood, we appreciate the nervous system’s ability to fine-tune its activities—much as we adjust the sound of a musical recording by fiddling with the many controls on a fancy stereo.

Vitamin B6 is part of the coenzyme needed to make the neurotransmitter GABA (gamma-aminobutyric acid), which makes neurons less sensitive to stimulation. Thus, a severe B6 deficiency can cause hyperexcitability of neurons and convulsions.*

Chemical transactions that occur at synapses have much to do with memory, mental illness, mood, drug addiction, etc. This is a burgeoning area of research (sales of antidepressants exceed a billion dollars per year in the U.S.).

It’s said that the center of the nervous system—the brain—is the last frontier of the human body. We know less about its workings than about any other body part. We expect that advances in this field will bring about ways to prevent and/or cure such malfunctions as the “storm” of nerve impulses in epilepsy, the severe memory loss of Alzheimer’s disease, and the sudden sleep that occurs in narcolepsy. Applications of new findings might be revolutionary. What if we could condense our need for sleep to an hour a night? (It wouldn’t be available to children—parents need the peace and quiet!)

^{*In 1951 and again in 1982, a commercial infant formula was inadvertently deficient in B6 . Many infants who were exclusively fed this formula developed muscular twitching and convulsions. FDA (Food and Drug Administration) scientist Dr. Oral Lee Kline recalled a study in which young B6-deficient rats developed similar symptoms, and correctly suspected that B6 was deficient in the formula. Most of the infants promptly recovered when given B6 . The 1980 Infant Formula Act requires that formulas meet nutrient standards; the FDA adopted quality-control procedures in 1982.}

Nerve-Muscle Junction

Synapses occur not only between neurons, but also between nerve and muscle, where nerve impulses cause muscles to contract (Figure 15.4). The neurotransmitter involved here is acetylcholine,† the first one discovered. It’s released at the nerve ending and attaches to receptors on the muscle cell, causing the muscle to contract. Acetylcholine is then rapidly broken apart by the enzyme acetylcholinesterase, enabling the muscle to return to its relaxed state (Figure 15.4). Unless acetylcholine—the stimulus—is removed, the muscle becomes hyperactive and can go into a spasm.

For centuries, South American Indians paralyzed their prey—man or animal—by poisoning the tips of their arrows with the curare- containing juice of a native plant. Curare attaches to acetylcholine receptors. This blocks the attachment of acetylcholine, thereby blocking the stimulus needed for the muscle to contract. The resulting paralysis can be “merely” incapacitating, so the victim can be approached and killed by other means. If the dose is high enough, the victim dies of respiratory paralysis. Curare-based drugs are among those used today in surgery as muscle relaxants; breathing is sustained by machine.

During the 1991 Persian Gulf War, it was feared that Iraq would use nerve gases—poisons that bind to acetylcholinesterase, the enzyme that breaks apart acetylcholine,* thereby causing muscle spasm. (Acetylcholine must be removed right after it attaches to its receptor on the muscle cell, so the muscle can relax; Figure 15.4.) Spasm of the respiratory muscles can be fatal.

Allied soldiers carried two kinds of antidotes in auto-injection devices, to be used within 2 minutes of exposure. One antidote relieves the spasms by attaching to the muscles’ acetylcholine receptors. The other breaks apart the nerve-gas-enzyme combination so that the enzyme is freed to do its job.

Although nerve gas wasn’t used in this conflict, its use in future wars or in acts of terrorism is still a threat. Better antidotes are being developed. Current ones have side effects, e.g., impaired sweating, impaired muscle coordination—not so good in the heat of battle.

One line of research is to make by biotech the part of the acetylcholinesterase enzyme that binds to the nerve gas, to be given as a drug before possible exposure. It would then already be in the blood, ready to attach to the nerve gas as it enters, thereby preventing the nerve gas from attaching to the actual enzyme.††

The disease myasthenia gravis (heavy muscle in Greek) involves the nerve-muscle synapse. In this autoimmune disease, the body sees acetylcholine receptors on muscle cells as foreign and destroys them. Early symptoms include muscle weakness and, sometimes, the inability to keep the eyelids open. Again, the greatest threat is respiratory paralysis. (Aristotle Onassis died of this disease.)

^{†Acetylcholine is made from acetate (acetyl CoA) and choline; both are abundant and easily made in the body. Acetate can be made from fat, carbohydrate, or protein (Chap. 9), and choline is a part of lecithin (Chap. 5), which makes up the basic structure of our cell membranes.
*A variety of substances can inhibit this enzyme. Some are used as insecticides. Flea powder commonly has such an inhibitor (a big dose for fleas, a small dose for dogs). Some inhibitors are being investigated as drugs for Alzheimer’s disease. (Acetylcholine also is a neurotransmitter at neuron-neuron synapses involved in memory.) In Alzheimer’s, acetylcholine-making neurons in the brain are damaged, leading to a deficit of acetylcholine—and memory. A drug-design strategy is to raise the level of acetylcholine at the memory-related synapses by hampering the enzyme that breaks it apart.
††This decoy-drug strategy is reminiscent of using biotech-produced CD4 (the attachment site on the cell membrane where HIV gains entry) as a decoy in hopes of preventing HIV from attaching to the “real” CD4 (Chap. 9).}

Stimulants

Stimulants like cocaine, amphetamines, nicotine, and caffeine generally increase alertness and improve mood. They vary in addictiveness (nicotine is the most addictive) and have different modes of action. Caffeine is a mild stimulant and its mood-enhancing effect, in particular, is much weaker than that of cocaine or amphetamines.

Many stimulants also suppress the appetite. This, combined with other effects that make people feel highly energetic, alert, and euphoric, has been especially useful in getting people to work hard under adverse conditions. When Spain invaded Peru in 1533, the invaders encouraged the Peruvian-Indian workers’ use of cocaine-containing coca leaf: “This herb is so nutritious and invigorating that the Indians labor whole days without anything else ....”

During World War II, amphetamines were used by both Axis and Allied soldiers, especially pilots. In Japan, they were also given to civilians to raise their wartime productivity. After the war, their use was encouraged in the Japanese population by Japanese drug companies stuck with large stockpiles. The result was a major epidemic of amphetamine addiction. In the late 1940s, about 1 in 20 Japanese between ages 16 and 25 was addicted.

The original Coca-Cola had both cocaine from the coca leaf and the caffeine-containing extract from seeds of the Cola acuminata tree. It was first served in Atlanta, Georgia (concocted in 1886 by an Atlanta pharmacist). Early advertisements said that Coca-Cola “put vim and go into your tired brain and body” and called it the “ideal nerve and brain tonic.” In 1903, cocaine was taken out of Coca-Cola, and more caffeine and some flavors from the coca leaf were added instead.

Caffeine

We ingest caffeine and caffeine-like substances in coffee, tea, chocolate, and some drinks and medications (Table 15-1).* Caffeine lessens fatigue and increases alertness and heart rate. Big doses (e.g., 1000 mg) can cause insomnia, nervousness, irritability, tremors, and headache (caffeine withdrawal also causes headache).

Table 15-1: Caffeine Content

People vary in sensitivity. Those who don’t routinely have caffeine are more sensitive to low doses. Also, caffeine is broken down less quickly as a person ages. Older people often refrain from drinking caffeinated beverages in the evening to avoid insomnia.

Caffeine’s health effects are unclear. It’s hard to sort out the specific effects of caffeine in population studies. Coffee and tea, for example, have substances besides caffeine that have various effects. Also, different varieties of coffee and tea as well as brewing methods affect a brew’s content.†

Also, certain habits are linked with drinking coffee (our main source of caffeine), making it hard to isolate the health effects of caffeine. People who smoke, for example, tend to drink more alcohol and coffee. The results of studies of coffee-drinking in relation to heart disease, cancer, and pregnancy are inconsistent. But the general consensus is that caffeine in moderate doses (about 200-250 mg/day, equivalent to about 2 cups of coffee) is safe, even during pregnancy.

Figure 15.4: Stimulation of Muscle Contraction

^{*Caffeine and caffeine-like substances are collectively called methylxanthines. Theophylline is the caffeine-like substance in tea; theobromine is in chocolate. Caffeine-like substances in tea and chocolate are commonly called caffeine.
†Some people worry about coffee decaffeinated with methylene chloride. However, ethylene chloride evaporates quickly, and any residual amount evaporates when coffee beans are roasted.}

Opioids

Opioids resemble opium (from the opium poppy) and include morphine, codeine, and the illegal drug heroin. The synthetic opioids fentanyl, oxycodone (OxyContin®), and hydrocodone (Vicoden®) are legally prescribed to alleviate pain. Opioids are highly addictive and easily abused. drugabuse.gov/drugs-abuse/opioids

We’re in the midst of an opioid crisis that was sparked in 1996 by Purdue Pharma (owned by the Sacker family) with its introduction and promotion of OxyContin®. In 2020, about 69,000 people in the U.S. died of opioid overdose.

Opioids work by attaching to opioid receptors in areas of the brain that control pain and pleasure. The brain can adapt to an opioid to the point where people have a hard time feeling pleasure without it. Withdrawal symptoms can be severe.

Many of the addicted started with a legitimate opioid prescription for pain and developed a dependence that led to buying illicit opioids, including heroin. “Street drugs” can include a mixture of drugs with uncertain dosages, which can more easily lead to accidental overdose. The musician Prince died in 2016 from an accidental overdose of fentanyl.

An overdose of opioids can cause death by slowing and stopping breathing. Naloxone (given immediately by nasal spray or injection) can rescue a person in this emergency by rapidly binding to the opioid receptors and blocking opioid’s effect.

Inhibitors/Depressants

Substances that inhibit nerve transmission include barbiturates, alcohol, and tranquilizers called benzodiazepines, e.g., Xanax®, Valium®. General effects are relaxation and reduced anxiety.

Barbiturates, once commonly used to treat anxiety, can also cause severe drowsiness, and a prescription-container-full is enough to commit suicide. Benzodiazepine tranquilizers are now commonly used instead to treat anxiety. Though addictive, they aren’t as addictive as barbiturates, and withdrawal symptoms aren’t as severe.

Also, large overdoses are rarely lethal. But combining them with alcohol can be lethal. Judy Garland (of Wizard of Oz), died from combining Valium and alcohol.

Many people combine opioids with benzodiazepines. Both can hamper breathing, increasing the risk of overdose. Over 30% of overdoses include a combination of opioids and benzodiazepines.

Alcohol

Although alcohol is absorbed by tissues throughout the body, the nervous system is particularly sensitive (Table 15-2). At low doses, we feel relaxed and cheerful—effects we associate with the pleasures of alcohol. As alcohol levels rise, the effects become those we associate with drunkenness—slurred speech, a staggered walk, and stupor.*

Table 15-2: Alcohol Effect on Nervous System

Long-term effects on the nervous system vary, depending on complex interactions between genetic susceptibility, toxic effects of alcohol, and alcohol-related malnutrition.

Those who chronically drink excessively can develop a tolerance for alcohol. Some develop such a tolerance that they seem sober at normally lethal blood-alcohol levels.

Withdrawal: Whether it’s large amounts of alcohol over a few days or smaller amounts over a long time, you can get withdrawal symptoms when you stop drinking or drink less (even if that lesser amount is still quite a lot). Symptoms vary in severity and can include tremors, nausea, vomiting, insomnia, confusion, nightmares, hallucinations, and seizures (the nervous system becomes overly sensitive to stimulation).

Wernicke-Korsakoff Syndrome is a degenerative brain disease, caused by a severe deficiency of thiamin (a B-vitamin). There’s severe mental confusion and memory loss. Many also walk in an unstable and uncoordinated manner and develop damage to nerves leading to the eyes, causing the eyes to tremor or become fixed into a stare.

In the U.S., the most common cause is alcoholism. Many alcoholics have diets severely deficient in thiamin (and other nutrients), and chronic drinking impairs the absorption, storage, and use of thiamin. Not all alcoholics with severe thiamin deficiency develop this disease, probably due to genetic differences.

If the disease is caught early, many of the symptoms can be reversed with immediate treatment with thiamin. Considering the cost of hospital treatment and the cost of nursing-home care for the permanently impaired, fortifying alcoholic beverages with thiamin as a means of prevention could be cost-effective.

Fetal Alcohol Effects: Fetal exposure to alcohol affects the developing brain and is thought to be a major cause of intellectual disability in the U.S. The full-fledged syndrome (Fetal Alcohol Syndrome) includes intellectual disability, a small head, growth retardation, abnormal facial features (e.g., eye-openings that aren’t as wide as normal), and other deformities. Although the full-fledged syndrome occurs in only about 6% of children of alcoholic mothers, milder forms of brain damage may occur in many more.

People sometimes think that if someone does not have the characteristically abnormal facial features of Fetal Alcohol Syndrome, the brain was not affected. But these facial features are formed during only a limited period during the first three months of pregnancy, whereas the brain is formed throughout fetal life and early infancy.

An unresolved question is whether moderate or low doses of alcohol, especially late in pregnancy, damage the fetus. Unlike deformities of the face or heart, subtle damage to neurons and their synapses isn’t easily measured. Even behavior and learning disabilities are hard to assess (it’s hard to distinguish alcohol effects from other environmental or genetic effects).

Fetal Alcohol Spectrum Disorder is used to describe the range of conditions that can occur in someone whose mother drank during pregnancy. cdc.gov/ncbddd/fasd/facts.html An estimated 10% of pregnant women drink during pregnancy.

Illogical behavior is common in alcohol-affected children. They literally act as if they aren’t properly “connected,” perhaps because alcohol interfered with the development of nerve pathways and synapses.

Although animal studies show that fetal alcohol exposure can have such effects as fewer dendrites on neurons (i.e., fewer connection sites), such subtle effects would be hard, if not impossible, to pinpoint in human studies.

Given the uncertainties, women who are pregnant or are trying to conceive shouldn’t drink any alcohol. Alcohol passes freely across the placenta—blood-alcohol level is the same in mother and fetus.

^{*After an auto accident, a driver who has been drinking will sometimes get out to “exercise,” hoping to burn off some alcohol before police arrive. Muscle tissue doesn’t break down alcohol; the liver metabolizes it at a leisurely pace. The driver might as well stay seated. About 30% of all traffic fatalities involve alcohol.}