NEURAL TRANSMISSIONS

Neural Transmissions
We know how electrical signals are generated – but how do they activate neuronal targets? If we compare neurons to electrical circuits, then the answer is clear. Each wire in a circuit connects to the next wire in a circuit and current flows uninterrupted through all of them. But very few neurons are connected together in this way. Instead, communication between neurons usually relies on neurochemical transmission. Where there are points of structural continuity between neurons, current can flow from one neuron to the next, just as it would from one wire to another that has been soldered to it. The electrical potential in one neuron then directly affects the electrical potential of the next, depolarizing the target neuron as though it were no more than an extension of the neuron in which the signal originated. Such connections – or gap junctions – do have some advantages. The signal is passed on at the maximum possible speed, and activity amongst groups of neurons is more easily synchronized, which can have its own advantages. But if all the neurons in our nervous system were interconnected in this way, whatever happened to one neuron would affect all the others and would at the same time be affected by all the others. This would radically reduce the system’s capacity for information processing. If all the neurons end up doing exactly the same thing, you might as well have only one neuron and be done with it. So to get the most out of each neuron, you want them to be able to operate to some extent independently. In particular, you may not want the activity of the target neurons to determine the activity of their own inputs. This problem of how to keep neurons independent and ensure that information flows in the right direction is solved by chemical neurotransmission. Chemical neurotransmission takes place at the synapse, across a very narrow gap called the synaptic cleft, where the axon of the input neuron most closely approaches its target both the axon terminal region and the post-synaptic membrane (i.e. the membrane on the target cell’s side of the synaptic cleft) are highly specialized. The axon’s terminal region contains small vesicles – packages filled with neurotransmitter. The neurotransmitter is released from the axon terminal, crosses the synaptic cleft and binds to specialized receptors in the membrane of the target neuron. For chemical neurotransmission to be fast, the chemical messengers need to be made of rather small molecules. The classical synapse in the brain is where an axon makes contact with the dendrites of its target neuron, although contacts from axon to axon and dendrite to dendrite are also known to occur. When an action potential reaches the axon terminal, some vesicles fuse with the external cell membrane of the neuron, and the neurotransmitter chemical they contain is released. Because the distance across the synapse is very small, the neurotransmitter rapidly diffuses across to the post-synaptic neuron, where it binds to its receptor sites. Stimulation of different receptor subtypes produces different physiological effects. For example, the classical acetylcholine receptor opens sodium ion channels, leading to a Nainflux that depolarizes its target cells, as described
earlier. Once a neurotransmitter has been released, two more events must occur. First, more of the transmitter chemical is synthesized in the cell body and transported along the axon to the terminal
region, ready for the next output signal. Second, the effects of the neurotransmitter in the target cell must be turned off again. Otherwise, a single input would depolarize its target forever, and no more information could be passed that way. A muscle, for example, would be left in a permanent state of contraction, whether it received a single impulse or a whole series of them. There are several mechanisms for deactivating neurotransmitters. The molecule might be degraded into a form that has no physiological effects. In the case of acetylcholine, this is done by the action of the enzyme cholinesterase, which completes the job within a millisecond. It can also be done by reabsorbing the neurotransmitter back into the axon terminal that released it, or by absorbing the neurotransmitter into an adjacent glial cell. You know by now that neurons’ output signals are all-or-nothing action potentials, and that a neuron must be depolarized beyond its threshold to generate an action potential. How are the neuron’s many different inputs combined? Input axons typically connect to target dendrites. The branching dendritic trees of some neurons may have as many as one hundred thousand synapses on them. At any moment, each of those synapses may be either active or inactive. Each active excitatory input will to some extent depolarize the target cell membrane around its synapse. But unless the target cell is depolarized all the way to its threshold potential, so that an action potential is generated, that individual excitatory input will not lead to any output from its target. The more inputs there are, the more sodium ions flow into the target cell, and the more likely it becomes that threshold potential will be reached. So the eventual activity of the cell depends on the overall pattern of activity of its many inputs. This means that, although neurons have all-or-nothing outputs, those outputs cannot control their targets in an all-or-nothing way. The effect on the target depends on the signals coming in at the same time from all its many inputs. In this way, neurons are effectively integrating their own inputs. Neurotransmission mechanisms are open to disruption. We can manipulate the receptors, or the transmitter release system, or the transmitter inactivation mechanisms. By designing drugs that affect the system in these ways, we can alter brain function. Curare is an Amazonian plant product. It paralyses movement by binding to the acetylcholine receptor on the muscles, and prevents acetylcholine released from motor nerves from reaching its intended target. Unlike acetylcholine, curare does not depolarize muscles, so the motor nerves can no longer cause muscle contractions. This loss of movement includes breathing. This is an example of an antagonist. Antagonists block the effects of neurotransmitters, often by occupying the transmitter’s receptor site. Curare was first used by South American Indians as a poison for hunting, but its synthetic derivatives are nowadays widely used in surgery. It can be very valuable for the surgeon to be able to control muscle movement and maintain respiration through artificial ventilation. Another way to produce essentially the same effects would be to block acetylcholine release. Botulinus toxin (from the bacterium clostridium botulinum, which sometimes grows in preserved foods that have been imperfectly sterilized) has this effect. It is one of the most lethal poisons known. You could kill off the entire human population of close to six billion people with about
28 grams of toxin. Nowadays it is sometimes used in cosmetic surgery to reduce brow wrinkles by paralysing the muscles under the skin. Neurotransmitter antagonists also have an important role in
psychiatry. The hallucinations and delusions in schizophrenia are often treated using dopamine receptor antagonists like haloperidol. Unfortunately, prolonged use of these drugs sometimes induces movement disorders as an unwanted side effect, by blocking the action of dopamine in the
nigrostriatal pathway. This is the pathway damaged in patients with Parkinson’s disease.

Neurotransmitter agonists are chemicals that have the same kind of action as the neurotransmitter
itself. If their action is irreversible, or much more powerful than the natural compound whose place
they usurp, then they are just as dangerous as powerful antagonists. They can equally disrupt function, by keeping signals permanently switched on. This can be done in several ways. Nicotine is a very widely used acetylcholine receptor agonist. It acts both centrally and peripherally. The lethal dose of nicotine for a human adult is 40–60 mg. There can be this much nicotine in just two or three
cigarettes, but smoking leads to much lower nicotine absorption than eating.

There are also indirect agonists, which work by inducing greater than normal neurotransmitter release, or preventing re-uptake. Amphetamine is a somewhat unselective, indirect dopamine agonist, which effectively increases dopamine release. Amphetamine abuse can lead to hallucinations
and delusions – essentially the opposite of the effect of haloperidol, described above. Direct neurotransmitter agonists also have an important role in neurology. Parkinson’s disease results from loss of dopamine neurons in the nigrostriatal system. One way to help restore normal movement in these patients is to boost dopamine function in the nigrostriatal pathway. This can be done by giving
apomorphine – a direct dopamine agonist, which simulates the effects of the missing dopamine. Or we can give a dopamine precursor, L-DOPA, which helps the surviving neurons to synthesize more dopamine. Too much L-DOPA can lead to terrible hallucinations. So clinical manipulations of dopamine activity need to manage some tricky balancing acts. A third way to increase neurotransmitters’ effects in the synapse is to disrupt deactivation mechanisms. So, although neurotransmitter is released perfectly normally, its period of effective action is abnormally prolonged. The result is similar to the effect of a direct neurotransmitter agonist. Cholinesterase inhibitors, which stop cholinesterase from performing its usual job of breaking down acetylcholine into inactive fragments, work in just this way. They are found in a number of plants and are widely used as insecticides. (They also form the basis of some of the most deadly nerve gases.) So the direct
acetylcholine agonist, nicotine, and the cholinesterase inhibitors are both synthesized by plants – presumably because they both make the plants toxic by overactivating the cholinergic systems of
animals that consume them. But they achieve this effect by two, quite different, biochemical routes.
These kinds of mechanisms can offer therapeutic benefits as well. Psychiatrists have for many years used monoamine oxidase inhibitors to treat depression. These drugs neutralize the enzymes that normally deactivate monoamine transmitters (noradrenaline, dopamine and serotonin). This increases the effectiveness of monoamine neurotransmission, leading to clear clinical improvements
after a few weeks of treatment.Although these drugs are still in clinical use, it is now more usual to treat depression with newer compounds that use a rather different mechanism aimed at prolonging the actions of monoamine neurotransmitters. Perhaps the best known is Prozac (fluoxetine). This is a specific serotonin re-uptake inhibitor (or SSRI). It reduces the re-uptake of a particular monoamine, serotonin, into the neuron from which it has been released. Once again, this means that whenever neurotransmitter is released, its effects on its targets are longer-lasting. So far we have considered only excitatory neurotransmission – how one cell induces an action potential in a target. But there is much more to chemical neurotransmission than signal amplification and one-way information flow. There are also inhibitory neurotransmitters, which reduce the excitability of a cell. If a cell has a constant but low level of incoming stimulation that keeps it firing at a regular rate, an inhibitory transmitter can reduce that firing. And if a target cell is quiescent, an inhibitory neurotransmitter can prevent it from being excited. The classic inhibitory neurotransmitter is GABA (gammaamino- butyric acid). GABA works by increasing chloride ion flow into the interior of the cell. Since chloride ions are negatively charged, they increase the cell’s negativity. This is called hyperpolarization. It is harder to excite an action potential in a hyperpolarized cell. Just as some drugs are designed to disrupt excitation, others work on inhibitory transmission to modify neuronal activity. Enhancing inhibition has much the same effect as disrupting excitation: both reduce neuronal activity. Yet because these two approaches depend on different chemical neurotransmitters, they can have rather different side effects. Among the various subtypes of GABA receptors is GABAA. This is a particularly interesting one, because it includes the site of action of the very widely used benzodiazepine minor tranquillizers – the class to which Librium and Valium belong. These drugs increase chloride flow into the cell. Alcohol and barbiturates act on other components of the GABAA receptor to have much the same effect, so in some ways they also act like
inhibitory neurotransmitters. It is an easy mistake to think of inhibitory neurotransmitters as simply inhibiting thought or action. But in a complex network of neurons, in which inhibitory projections may inhibit other inhibitory cells, it is hard to predict the eventual outcome of inhibiting neuronal activity. Nonetheless we can generalize about the effects of blocking inhibitory GABA transmission. Drugs that do this tend to produce epileptic seizures. Equally, drugs that enhance inhibitory transmission can be used to prevent epilepsy. If a patient has been treated for a long time with drugs that increase GABA transmission and that treatment is suddenly stopped, there is a risk that the patient may suffer from epileptic convulsions. So at some very general level, inhibitory transmitters do damp down the excitability of the brain. Some of the most horrific poisons, like strychnine, produce their effects by preventing inhibitory transmission (in this case at glycine-dependent inhibitory interneurons in the spinal cord).