Transmitters

Most of the findings of the quiet revolution date from the mid-1960s through the 1970s, when the electron microscope first became available to researchers. They are still not widely discussed outside the field of neuroscience, probably because of the complexity.

In the 1980s, another revolution occurred in neuroscience. This one was loud in comparison to the first. (In other words, more people have heard about it.)

The second revolution had a huge effect on scientists' understanding of how drugs work and what causes certain types of mental illness. The focus was upon neurotransmitters, also known as transmitter substances or just transmitters

What are three different names for transmitters?

First, let us revisit the synapse, which we described earlier as an area where two neurons come very close together. The word synapse actually refers to the area on both sides of the gap between neurons, plus the associated structures.

What areas are considered part of a synapse?

The synapse includes the presynaptic (before-the-synapse) area, the postsynaptic (after-the-synapse) area, plus associated structures (such as thickenings which occur on both sides of the synapse). It also includes the cleft which separates presynaptic and postsynaptic areas.

Gap junctions are synapses without such a cleft. However, most synapses are the chemical type, with a small gap and no direct junction. The cleft is very small–about 200 angstroms–so chemicals diffuse across it almost immediately. An artist's depiction of this process is shown in following figure.

Transmitters are released into the synaptic cleft

Chemicals are stored on the presynaptic side of the synaptic cleft, in containers called vesicles (VESS-ik-ulls). Vesicles are little spheres made of membrane. One neuroscientist (Palay) said they are like chocolates, coming in a variety of shapes and sizes with different fillings.

The "fillings" inside vesicles are the transmitters. Because the chemicals are stored in vesicles only on one side of the synapse (the presynaptic side), each chemical synapse is a one way street. The nerve impulse can be propagated only from the side with the vesicles to the side without.

What do vesicles contain? Why is a synapse a one-way street?

When a nerve impulse arrives at a chemical synapse, transmitters are released from the vesicles. They rapidly cross the synaptic cleft and bind with receptor sites on the post-synaptic (after-the-synapse) neuron.

A common metaphor used in describing receptor sites is locks and keys. Transmitter substances are little keys that fit into particular locks, receptor sites with specific shapes.

Specific transmitters match with specific receptor sites. After being used, the vesicle and its contents are recycled, with the chemicals sent back to the presynaptic side.

As vesicles are created, they are filled with transmitter substances recycled from the postsynaptic side after being used. This is called "re-uptake." Within a minute, vesicles on the presynaptic side are ready to release the chemicals again (Betz & Bewick, 1992).

When the transmitter reaches the postsynaptic neuron and lodges in the receptor sites, it typically alters the postsynaptic neuron's permeability to ions. Depending on which ion species are involved, this may make the postsynaptic neuron more likely or less likely to fire a nerve impulse itself.

What process occurs when the nerve impulse arrives at a synapse?

In most cases, firing a neuron either stimulates other neurons (makes them more likely to fire) or inhibits them (makes them less likely to fire). Each synapse is either excitatory or inhibitory.

We will discuss a few major transmitters in the pages ahead. In the 1960s there were three widely recognized transmitter substances: acetylcholine (assiteel-KOH-leen or a-SEE-tyl-koh-leen), norepinephrine (NOR-ep-en-EF-rin) and serotonin (sara-TOE-nin).

Next came Gamma-aminobutyric acid (GABA, pronounced as it appears). Then the dam broke: large numbers of small peptides were identified as possible transmitters. Now over a thousand are known.

Manipulation of Neurotransmitters

Neurotransmitters and neurohormones are involved in everything we do. To study them, researchers manipulate their levels around the synapse.

Researchers found many ways to alter levels of transmitters. Chemicals used by researchers may...

–interfere with a neurotransmitter's synthesis; this lowers its levels.

–provide an artificial transmitter that has the same effect as a natural transmitter (this raises transmitter levels).

–stimulate synthesis of a "false transmitter" that competes with the real transmitter for places on the postsynaptic membrane (this reduces the effects of the real transmitter).

–block removal of the transmitter. Normally transmitter substances are recycled. This is called re-uptake of the transmitter. If the recycling operation is blocked, excess transmitter gathers in the area of the synapse (this raises transmitter levels).

–cut down on calcium around the synapse, which prevents release of the transmitter substance from the vesicles (this lowers transmitter levels).

–provide the re-uptake system with "dummy" neurotransmitters that don't work when released (this lowers transmitter levels).

The result is always one of two things: increasing or decreasing the amount of active transmitter at a synapse.

What "two things" are the result of manipulating transmitter levels?

Blocking or accumulation of transmitters may occur in roundabout ways. Consider the case of caffeine, the active ingredient in coffee. Caffeine has a molecular shape similar to adenosine, a transmitter.

Adenosine normally makes us sleepy. Caffeine is able to occupy receptor sites on the postsynaptic membrane where adenosine would normally go.

When caffeine occupies the receptor sites, adenosine cannot exert its usual inhibitory action. Thus caffeine wakes us up by blocking a transmitter (adenosine) that normally makes us sleepy.

How does coffee achieve its effect? Why was the mouse "laid back"?

An adenosine mimic is a chemical that has the same effect as adenosine. If coffee achieves its stimulatory effect by blocking adenosine, you would expect an adenosine mimic to make animals sluggish.

mouse sitting on its fanny
"Laid back mouse: A mouse treated with an adenosine mimic has lost its 'get-up-and-go'."

Sure enough, a mouse treated with an adenosine mimic was reported to "lie around loose, relaxed, and splayed out, but wide awake and responsive to painful stimuli." A cup of coffee would have put it back on its feet (Marx, 1981).

Acetylcholine

The first transmitter discovered was acetylcholine, pronounced either assiteel-KOH-leen or a-SEE-tyl-koh-leen. The chemical name is abbreviated ACh. It is a combination of choline and acetic acid, distributed widely in the brain, involved in many important brain systems called cholinergic (kohleen-URGE-ik) pathways.

What is ACh? AChE?

Like other transmitters, acetylcholine must be removed from the synaptic cleft, once it has done its job. Acetylcholinesterase, abbreviated AChE, is responsible for this. It breaks ACh into the components choline and acetic acid, neither of which is active at the synapse.

The choline is absorbed back into the presynaptic cell, made into ACh, and stored again in the vesicles. As noted earlier, in the list of ways to alter transmitter levels at the synapse, this is called re-uptake of a transmitter.

How do most insecticides work?

AChE, the chemical that breaks ACh into its components, is "knocked out" by chemicals called cholinesterase (kohleen-ESTER-ase) inhibitors. When cholinesterase is inhibited, ACh builds up at the synapses. That causes disordered nerve activity.

Read the fine print on the label of any insecticide and you will probably see the words "cholinesterase inhibitor." For insects, the effect on ACh-using neurons is fatal.

Cholinesterase inhibitors are commonly sprayed around households, businesses, and schools in order to control pests like cockroaches. This is unnecessary (bait trays provide a safe and effective alternative).

I humbly predict that within 50 or 100 years the practice of spraying cholinesterase inhibitors around our living spaces will be regarded as incredibly foolish. Acetylcholine is one of dominant transmitters in humans as well as insects. Problems with cholinergic pathways are linked to Alzheimer's Syndrome and a variety of other disorders.

Why might it be incredibly foolish to spray these around our homes and businesses?

One common insecticide targeting acetylcholine is malathion (mal-a-THY-on). Communities in the southeastern United States spray it freely to combat mosquitoes.

Our hometown paper published a photograph of small children playing in the fog behind a truck spraying malathion. Chemical companies assert that malathion is harmless to humans, but they have an interest in fostering that belief. I tend to believe we take unnecessary risks by putting nerve poisons in our environment.

Dopamine

After acetylcholine, the next transmitters discovered were the catecholamines (CAT-a-COLE-a-means). Two important members of this transmitter family are dopamine and norepinephrine.

Dopamine is found in two areas of the midbrain, the tegmentum and the substantia nigra. These are both parts of the limbic system, the portion of the brain regulating emotion, particularly the response to reinforcement, pleasure, and addictive stimuli.

Dopamine is involved in the response to cocaine. Rats will press a bar many times to get cocaine injected directly into dopaminergic areas of the limbic system (areas heavily laden with neurons using dopamine). The same is not true of other brain areas.

What is evidence that dopamine is involved in the effects of cocaine?

When researchers destroy dopaminergic areas of the limbic system of rats, the rats no longer find cocaine reinforcing. Dopamine is also implicated in the brain's response to addictive behaviors, including learned preferences.

This includes pleasures that are not usually regarded as harmful addictions, such as intense pleasurable responses to music, victory in sports, and religious devotions such as meditating and praying. All "light up" the dopaminergic circuits of the brain.

Dopamine was thrust into public attention when L-Dopa–a drug that restores dopamine synthesis–was discovered as a treatment for Parkinson's disease. L-Dopa was the drug that Oliver Sacks used to bring patients out of a semi-comatose state (temporarily, as it turned out) in the book Awakenings.

Too little dopamine produces symptoms of Parkinson's disease, but too much produces psychosis (serious mental illness often requiring hospitalization). Antipsychotic drugs used widely in mental hospitals all have the property of blocking dopamine receptors.

Too much L-Dopa, in treatment of Parkinson's disease, can produce psychotic symptoms. The patients in Awakenings who received L-Dopa developed psychotic symptoms, in some cases.

What is L-Dopa? What evidence links dopamine to motor control systems?

Dopamine is implicated in motor control systems. Freed and Yamamoto (1985) injected specially marked dopamine into moving animals. The dopamine accumulated in motor control areas. The area where it accumulated depended on the speed, direction, and posture of the moving animals.

Norepinephrine

A second major catecholamine, norepinephrine (NOR-ep-in-EFF-rin) resembles adrenaline in its action. It is secreted into the bloodstream during moments of exertion or other stress.

For example, inescapable footshock produces immediate boosts of norepinephrine in the blood of rats. Normally, adrenaline helps the fight or flight response of the sympathetic nervous system.

What does norepinephrine resemble?

Elevated levels of catecholamines produce activity and euphoria. Cocaine and amphetamines work not only by stimulating dopaminergic areas but also by blocking re-uptake of norepinephrine, causing it to accumulate so it has an exaggerated excitatory effect.

Over the long term, elevated levels of dopamine and norepinephrine produce "burn-out." In extreme cases, stimulant abusers present symptoms closely resembling a paranoid psychosis, such as suspicion, hostility, and hallucinations of bugs under the skin.

Serotonin

Serotonin (sara-TOE-nin), technically known as 5-hydroxytryptamine or 5-HT, was one of the first neurotransmitters discovered. During the 1960s, researchers noticed that serotonin resembled LSD in chemical structure.

Reducing serotonin levels in rats with special toxins (selective poisons) produced symptoms associated with "bad trips." Rats become hyperactive, frightened by novel environments, and generally anxious in appearance and behavior (Ellison, 1977).

Not all serotonin-reducing drugs have this effect, however. Several types of serotonin receptors exist. Some compounds block serotonin more profoundly than LSD without producing psychoactive effects.

Serotonin may also be involved in other changes of mood and consciousness. For example, serotinergic receptors are prominent in the raphe nuclei of the brain stem, which regulate sleep and dreaming.

What are indications that serotonin can alter mood or emotion? What are serotonin re-uptake inhibitors used for?

Prozac, an anti-depressant medication that became popular in the mid-1990s, works by raising serotonin levels. An herb called St. John's Wort works the same way. Its effects are milder and slower to occur than prescription antidepressants. Nevertheless, St. John's Wort was for many years the most-used herbal remedy in Germany.

Many anti-depressive medications are selective serotonin re-uptake inhibitors (SSRIs). They inhibit the breakdown and recycling of particular varieties of serotonin. This causes serotonin to accumulate around synapses. For some people, this provides relief from depression.

GABA

GABA (Gamma-aminobutyric acid) was the first new transmitter to be discovered after the three "classic" transmitters (norepinephrine, acetylcholine, and serotonin). It is one of the most frequently occurring transmitters in the central nervous system.

GABA usually has an inhibitory function. Sedative-hypnotic drugs like barbiturates act by stimulating release of GABA-like substances. When GABA levels are too low, seizures may occur.

What is the usual effect of GABA?

Valium and the class of tranquilizers it represents, benzodiazepines, act on the GABA-related transmitter systems. The benzodiazepines and the barbiturates are quite different in their structure, clinical effects, and mode of action...but they both reduce anxiety, and apparently both do it by boosting levels of GABA.

GABA is sometimes described as a "downer" transmitter that counteracts glutamate, a transmitter associated with stimulation. GABA is involved in many drugs that have a sedative effect.

GABA itself does not cross the blood-brain barrier, which keeps harmful substances out of the brain's cerebrospinal fluid. GABA supplements taken orally have no psychological effect.

Brain Peptides

The first chemicals identified as transmitters were relatively simple substances. All except acetylcholine consisted of a single amino acid or its derivatives.

Beginning in the mid-1970s, researchers began to suspect many other substances were transmitters. Most were peptides: strings of amino acids. Once scientists began looking at peptides as potential transmitters, they kept finding more.

The first neuropeptide to be discovered was a sequence of 12 amino acids called substance P. It is a transmitter of pain signals, among other things. Substance P also has a role in regulation of mood disorders, anxiety, neurogenesis, neurotoxicity, respiratory rate, and nausea.

What does substance P do, among other things? Is it rare or common, in brain tissue?

Substance P was discovered by accident in 1931 when researchers were trying to isolate a different compound. Two researchers at Brandeis University pinpointed its chemical structure in 1970. Substance P is found in virtually all brain tissue.

Nitric Oxide, Glutamate, and Neuroimmunology

An unexpected finding in neuroscience was that nitric oxide (NO) could function as a transmitter substance. Nobody expected a gas to be a transmitter, but it is. It is broken down very rapidly after it is released, which is one reason nobody discovered it before the 1990s.

Why was the discovery that NO worked as a transmitter unexpected?

Nitric oxide the transmitter is not to be confused with nitrous oxide (N²0), the so-called "laughing gas" used by dentists as an anesthetic. The transmitter nitric oxide (NO) is a lighter gas with one unpaired electron. It reacts vigorously with other molecules, and it vanishes within 4 to 5 seconds in the presence of oxygen.

After its discovery, nitric oxide was found to be involved in many important processes. It was proclaimed "molecule of the year" by the journal Science in 1992.

Glutamate is a neurotransmitter that interacts with nitrous oxide and often causes nitric oxide to be released. Glutamate is familiar to many people as an ingredient of monosodium glutamate (MSG), the flavor-enhancing food additive.

Glutamate is neurotoxic (nerve-damaging) in large doses. Some people claim to be allergic to monosodium glutamate used in foods. Scare stories on the internet warned people to avoid foods with MSG. Food manufacturers responded by removing the chemical from ingredient lists. They substituted yeast extract, a natural source of MSG, and now yeast extract is commonly included in many foods..

MSG or yeast extract used in moderation is probably not dangerous. Glutamate is common and important in the nervous system; it is released by about 90% of neurons during excitation (Magistretti, Pellerin, Rothman, and Shulman, 1999). The release of glutamate leads to a cascade of chemical events, including the consumption of glucose picked up on PET scans.

Where is glutamate found, in a food additive? Is it rare or common, as a transmitter?

As a transmitter, glutamate fits into receptor sites like the proverbial key into a lock. An important type of glutamate receptor is the NMDA receptor. Mild stimulation of the NMDA receptor results in strengthening a synapse, part of learning and memory. However, overstimulation of NMDA receptors can cause neurotoxicity or the killing of neurons.

Why are medical researchers interested in blocking NMDA receptors?

Some of the damaging after-effects of stroke and brain injury are due to excessive release of glutamate and the excessive activation of NMDA receptors. If glutamate release (or NMDA reception) can be suppressed after a brain injury, the extent of injury is reduced.

Endorphins

In 1976, the normally staid journal Science reported that researchers were "High on Endogenous Opiates" (Marx, 1976). Scientists were excited about their discovery of substances in the human body that belonged to the same chemical class as opium, morphine, and heroin (opiates).

Endogenous opiates are usually called endorphins. The word endogenous means naturally occurring within the body.

Like other opiates, endorphins are painkillers, over the short term. The body produces endorphins in response to stressful events such as unavoidable electric shocks, sudden injury, or (for pregnant women) going into labor.

Soldiers generate endorphins in their bodies when they go into battle. That partly explains why soldiers sometimes continue to fight despite injuries.

In general,stress raises endorphin levels. For example, if researchers expose rats to inescapable footshock in an electrified metal cage, endorphin levels rise.

What are "endogenous opiates" and what causes their release in the body?

One might assume that endorphins are an automatic response to pain, but apparently this is not the case. Early endorphin researchers were surprised to find that a laboratory test that produces acute pain, dipping an arm into ice water, produced no change in endorphin levels (Grevert and Goldstein, 1978).

Perhaps the laboratory situation separates stress from pain. It is painful but not stressful, because subjects realize it is an experiment and will soon be stopped.

It may be psychological distress rather than physical pain that causes "stress" as most people use the term. Only pain that is perceived as unpleasant and unavoidable triggers endorphins. Those conditions are not present when dunking an arm in ice water, voluntarily, for the sake of science.

As endorphins have become widely known, they acquired a popular image not corresponding to reality. For example, one musician commented in an interview that he felt "a little burst of endorphins in my brain" when improvising with other musicians.

No doubt he meant that he felt joy in creating music. If he really experienced a burst of endorphins, he would feel numb, not excited. Endorphins are not pleasure chemicals; they are painkillers.

What are myths about endorphins?

Another myth is that endorphins are responsible for the jogger's high reported by long-distance runners. The idea is plausible: long-distance running is a form of stress on the body that might conceivably produce endorphins. However, this is a case of physical stress not accompanied by negative emotions.

Sure enough, research showed that jogging was not accompanied by bursts of endorphins. Joggers given naloxone, a substance that blocks endorphins, continue to experience a runner's high (Trotter, 1984).

How did research with naloxone demonstrate about placebo based pain relief?

The same sort of experiment showed that endorphins are produced by pain-killing placebo effects (pain relief due to belief in a medical treatment). In one study, patients receiving a sugar pill placebo at a dental appointment were randomly assigned to receive naloxone or an inert substance.

When patients did not receive the naloxone, they experienced pain relief from the sugar pill. It was equivalent to a standard hospital dose of morphine, although entirely self-generated. When they received naloxone, this effect did not occur (Rensberger, 1987).

Although opiates are known as painkillers, over a longer time period, they have the opposite effect. They sensitize the body to pain. That is called opioid-induced hyperalgesia (Lee, Silverman, Hansen, Patel, and Manchikanti, 2011).

In one study, volunteers receiving treatment for opiate addiction participated in the standard laboratory test of pain: dunking an arm in ice water. Normal people withstood this for about two minutes. People with a history of opiate addiction averaged only about 15 seconds (Servick, 2016).

What is opioid-induced hyperalgesia?

In 2016, the number of overdose deaths from opiates passed the number of gun-related deaths in the United States. Increasingly, researchers cautioned again giving opiates to people with moderate pain.

Opiates are valuable in the most extreme cases (such as cancer patients near death). They work when nothing else is effective. However, for users with moderate pain, opiates are a trap. They provide momentary relief but make people less able to withstand pain later. For obvious reasons, this contributes to dependency and addiction.

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References:

Betz, W. J., & Bewick, G. S. (1992). Optical analysis of synaptic vesicle recycling at the frog neuromuscular junction. Science, 255, 200-203.

Ellison, G. D. (1977). Animal models of psychopathology. American Psychologist, 32, 1036-1045

Freed, C. R. & Yamamoto, B. K. (1985). Regional brain dopamine metabolism. Science, 229, 62-65.

Grevert, P. & Goldstein, A. (1978). Endorphins: Naloxone fails to alter experimental pain. Science, 199, 1093-1094.

Lee, M., Silverman, S. M., Hansen, H., Patel, V. B., & Manchikanti, L. (2011) A comprehensive review of opioid-induced hyperalgesia. Pain Physician, 14, 145-161.

Magistretti P .J., Pellerin, L., Rothman, D. L., & Shulman, R. G.. (1999) Energy on demand. Science, 283, 496-497.

Marx, J. L. (1976). Neurobiology: Researchers high on endogenous opiates. Science, 193, 1227-1229.

Marx, J. L. (1981) Caffeine's stimulatory effects explained. Science, 211, 1408-1409.

Rensberger, B. (1987, January 19) Placebo's effect on pain may equal a dose of morphine. Washington Post, p.A4.

Servick, K. (2016) Primed for pain. Science, 354, 569-571.

Trotter, R. J. (1984, May). Rethinking the high in runner's high. Psychology Today, p.8.

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