A Tour around Neurotransmitters

(Date of publication 31 August 2005)

Strange though it may seem, neurotransmission was being blocked by Amazonian Indians centuries before the concept even existed in the developed world; 16th century European explorers discovered tribes using curare as an arrow poison to paralyse their quarry, and Sir Walter Raleigh brought some back to Queen Elizabeth I in 1584. History does not record whether she found a use for it! Curare interferes with acetylcholine, the most abundant neurotransmitter, but there are many others with a wide range of functions.

Neurotransmitters are chemicals made by nerve cells (neurones), to transmit signals to other neurones or non-neuronal cells (e.g. muscle or gland cells) which they innervate. The basic process is shown in this simple diagram. The gap between the two cells is extremely small: approximately 0.02 of a micron, as indicated in this electron micrograph. Where the junction (or synapse) is between two neurones, the nerve impulse arrives from the presynaptic neurone and passes to the postsynaptic neurone, where the neurotransmitter binds to membrane receptors. These are large proteins anchored to the cell membrane. The effect is to alter the flow of ions across the membrane, making the post-synaptic cell more likely to become depolarised and transmit the signal if the neurotransmitter is excitatory, or less likely if the neurotransmitter is inhibitory.

Acetylcholine is a chemical transmitter of the central nervous system (CNS) and parasympathetic nervous system, and is particularly important in the stimulation of muscle tissue. It has an excitatory effect in the brain, stimulates striated muscle to contract and, via the parasympathetic system, increases the secretion of glands and slows the heart. After its release it is quickly broken down by the enzyme acetylcholinesterase into acetate and choline, which pass back to the pre-synaptic neurone to reform acetylcholine. Some nerve agents act by inhibiting acetylcholinesterase, thereby causing acetylcholine to accumulate and continually stimulate the muscles, glands and CNS.

In myaesthenia gravis, sufferers develop an autoimmunity to nicotinic acetylcholine receptors, causing muscular weakness that worsens with exercise and improves with rest. The condition is often associated with a thymoma, and anti-receptor antibodies are present in about 85% of patients. Maximum muscle weakness usually occurs within 3 years before it plateaus or improves – there is a spontaneous remission rate of around 20%. In Alzheimer's Disease, the chemical defect that produces the most striking symptoms is acetylcholine depletion, contributing significantly to loss of memory and reduced attention span. Moreover, recent research indicates that this is because acetylcholine reduces the production of interleukin-1 and other inflammatory compounds, which have a destructive effect on the brain.

In the sympathetic nervous system, the neurotransmitter dopamine increases heart rate and blood pressure, but in the CNS it is associated with pleasure and motivation – its release produces feelings of enjoyment when triggered by experiences such as sex and eating – as well as control of movement and neurocognitive functioning. However, dopamine is not simply a 'reward' chemical but now appears to be predominantly involved in desire rather than pleasure. Cocaine and amphetamines both have their effect by greatly increasing the amount of dopamine in certain areas of the brain, but utilise different mechanisms. These drugs can cause psychosis by disrupting the dopamine system, and all modern anti-psychotic medication is designed to block dopamine function to varying degrees.

Parkinson's Disease is now thought to be due to a deficiency of dopamine in the basal ganglia of the brain, caused by the loss of neurones which produce it. The major symptoms are muscular rigidity, resting tremor, difficulty in initiating movement and problems with balance and walking. Dopamine itself cannot cross the blood/brain barrier, but its precursor L-DOPA can alleviate symptoms, although its therapeutic effect gradually diminishes. This article is somewhat dated but has a wealth of information on the condition. A newly-discovered dopamine pathway suggests that prolonged exposure to high levels of the compound may be associated with depression and could explain the impact of drug abuse on the brain.

Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter present in the CNS and gastrointestinal tract which is thought to play an important part in the biochemistry of depression, migraine, bipolar disorder and anxiety. Various psychiatric medications, including monoamine oxidase inhibitors, tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) affect serotonin levels. This last group, of which Prozac is the most well known, acts by slowing down the reuptake of serotonin by the pre-synaptic neurone. The advantage of these compounds is that the toxic dose is high and the side effect profile good. Earlier this year it was discovered that SSRIs also 'hijack' dopamine transporters so that a dopamine-triggered impulse results in the release of both dopamine and serotonin.

Norepinephrine, or noradrenaline, mediates communication in the sympathetic nervous system in response to short term stress, increasing the heart rate and blood pressure. Emotionally, this transmitter also appears to maintain the balance between agitation and depression. Low levels are associated with a loss of alertness, poor memory and depression, while sudden severe increases are linked to panic attacks. Many patients with low norepinephrine levels are treated with the new serotonin-norepinephrine reuptake inhibitors (SNRIs), which increase the levels of both neurotransmitters.

Having spent this tour familiarising ourselves with the basic concepts, it now appears that nerve cells can also communicate by releasing neurotransmitters at sites distant from the synapse, and this so-called "ectopic neurotransmission" could account for up to 90% of neural signalling. It looks as though this tour could become obsolete very, very quickly.....

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