Introduction
Transmission refers to the transferring of signals from a source to a receiving end through or across a medium. Synaptic transmission specifically refers to the transferring of a signal from a neuron
(a nerve cell) across a space called the synaptic cleft to a target cell. The nerve impulse is generated in the cell body of the neuron and is related to the movement of sodium ions across the cell membrane of the axon (the axon is an extension of the neuron cell body). This impulse is known as an action potential. When the impulse reaches the axon terminal, this presynaptic signal either remains as an electrical signal or is converted to a chemical signal; either way, it is then transmitted through this space and exerts an influence on the target cell. The synapse contains three areas: the presynaptic terminal, the synaptic cleft, and the postsynaptic membrane.
Physical activity and behavior involve neuronal activities and the resulting contractions and relaxations of many muscles. The winking of an eye, for example, involves the control of contraction and relaxation of eyelid muscles. The axon terminals of the motor neurons must synapse with the eyelid muscles. A synapse between neuron and muscle cells is called a neuromuscular junction. The axon terminal releases a neurochemical that acts on the receptors embedded in the cell membrane of the postsynaptic muscle cells, resulting in muscle contraction. The synaptic area is a key to the control of neural effects; most chemicals that affect the nervous system vary physiological and behavioral responses at this site.
Electrical and Chemical Modes
Two distinct modes of synaptic transmission have been delineated, one electrical and the other chemical. At an electrical synapse, the presynaptic current spreads across the intercellular gap to the target cell. For this spreading to occur, a low-resistance pathway is required; this is achieved by a close apposition of cells with a gap of about 2 nanometers (1 nanometer is one-billionth of a meter). This type of coupling is called a gap junction. In electrical transmission, unlike chemical transmission, an impulse in the presynaptic terminal is transmitted to the postsynaptic terminal with little attenuation (lessening) and with no time delay. Electrical synapses are very common in the nervous systems of invertebrates, lower vertebrates, and embryonic animals.
At a chemical synapse, the gap is about 20 to 30 nanometers. The high resistance does not allow the presynaptic current to spread to the postsynaptic current. On arrival of impulses, a presynaptic terminal releases chemicals termed neurotransmitters. These molecules then diffuse through the cleft and interact with receptors, complex protein molecules embedded in the postsynaptic membrane. The neurotransmitter molecules are stored in vesicles. The wall of the vesicle becomes fused to the presynaptic membrane because of the influx of calcium ions on arrival of the impulse; this results in release of the molecules. The interaction between neurotransmitter and receptor results in certain electrical and chemical events in the target cell. In chemical transmission, the signals are attenuated, and the process takes more time than electrical transmission—about 0.3 millisecond, which is termed the synaptic delay. Neurotransmitters secreted by the presynaptic terminals include acetylcholine, dopamine, epinephrine, norepinephrine, serotonin, certain amino acids (gamma-aminobutyric acid, glutamate, glycine, aspartate), and many peptides.
Neurons come in various shapes and possess varying numbers of branches. Basically, however, each consists of the dendrites, the soma (cell body), and the axon. Synapses are classified in terms of the nature of the presynaptic terminal and the postsynaptic end. The presynaptic terminal is usually an axon; however, it has been found that dendrites may communicate with other dendrites directly at a synapse termed a dendrodendritic synapse. Three types of synapses between neurons are axodendritic, axosomatic, and axoaxonic. An axodendritic synapse couples an axon terminal to a dendrite of another neuron and usually produces a depolarization or excitatory postsynaptic potential. An axosomatic synapse couples an axon terminal to the soma of another neuron, and it may produce a hyperpolarization or inhibitory postsynaptic potential as well as an excitatory postsynaptic potential. An axoaxonic synapse couples an axon terminal to another axon terminal, which results in reduction of excitatory postsynaptic potential in the target neuron of the second neuron, so the net effect is inhibitory. When an axon terminal is coupled to a muscle cell or a glandular cell, the synapse is called a neuromuscular junction or a neuroeffector junction. The excitatory postsynaptic potential occurring in the muscle is called end-plate potential. When the sum of those potential changes reaches the threshold of firing, an action potential is generated, resulting in a propagating impulse or muscular contraction.
Studying the Nervous System
The release of a neurotransmitter substance, the binding of neurotransmitter molecules to receptors, and the termination of neurotransmitter activities are among the key considerations in understanding the regulation of the effects of the nervous system. The synthesis and storage (in vesicles) of these substances are also important. The magnitude and duration of many physiological and behavioral responses are jointly determined by various neuronal effects. Neuroactive drugs are crucial tools, and various ones manipulate different phases of transmission, synthesis, storage, release, binding, and termination of neurotransmitters. These drugs may be used to study the functions of various neurochemicals as well as to control synaptic transmission for therapeutic purposes.
Neuroactive drugs and chemicals are classified in terms of their facilitating or inhibitory effects. Agonists are those that enhance the effects of a neurotransmitter; antagonists inhibit the effects. For example, curare, a compound extracted from a vine by South American Indians for use as an arrow posion to paralyze animals, is an antagonist of the neurotransmitter acetylcholine at the neuromuscular junction. Curare interferes with synaptic transmission at this junction, resulting in muscle paralysis.
A lock-and-key analogy is often employed to explain how synaptic transmission works. The neurotransmitter molecule represents the key, and the receptor molecule represents the lock. Just as the correct key is needed to open the lock on a door, the appropriate chemical “key” is needed to start the effect. The molecular lock has the recognition site and the active site as well as the support structure, just as the door has the keyhole with specific notch configurations, as well as other parts. A neurotransmitter may be able to open several different locks, termed receptor subtypes, which are named for the chemical compounds specific to each subtype. (In this sense, a neurotransmitter is like a submaster key that will fit several doors, while a subtype-specific compound is the key for only one door.) The neurotransmitter acetylcholine, for example, acts on two receptor subtypes—nicotinic and muscarinic. The nicotinic receptor is so named because it reacts specifically to nicotine, a substance found in tobacco. This receptor subtype is found in the smooth and cardiac muscles; the muscarinic subtype, on the other hand, is abundant in the brain.
Nicotine and muscarine, in other words, each affect only one subtype, but acetylcholine affects both; thus, acetylcholine and nicotine are both nicotinic receptor agonists, and acetylcholine and muscarine are both muscarinic receptor agonists. To return to the example of curare, it is a subtype-specific blocker that acts on the nicotinic receptor to block the effect of acetylcholine, causing paralysis of the skeletal muscles. Chemical variants of curare are used clinically to cause muscle relaxation before surgery.
Atropine is a muscarinic receptor blocker, so the cholinergic effects that are mediated by this subtype are antagonized. This drug is used to reduce motion sickness, to induce pupillary dilation for retinal examination, and to fight the sickening effects of certain gases used in chemical warfare. It is because those gases often involve cholinergic agonists that atropine is an appropriate antidote. There are many other compounds that can affect cholinergic effects through interfering with the release, receptor binding, and termination mechanisms. For example, the venom of the black widow spider facilitates the release of acetylcholine, whereas botulinum food poison inhibits its release. Physostigmine, a compound obtained from the Calabar bean in West Africa, enhances acetylcholine effects. Physostigmine is used to treat glaucoma and to help control the forgetfulness of Alzheimer’s disease patients.
Synthetic Neurotransmitters
The potency and efficacy of a drug are presumably related to the degree of fit between the drug molecule and the receptor molecule; a potent drug is one with a good fit to a receptor or subtype. The pharmaceutical industry is constantly working to synthesize variants of neurotransmitters and neuroactive compounds to make the effects of the drug both potent and specific, thus reducing undesirable side effects.
Because acetylcholine in the brain is known to be related to learning and memory, and since Alzheimer’s disease
involves memory loss, it is theorized that the disease may involve cholinergic subfunctioning. Indeed, cholinergic neurons have been found to be lacking in Alzheimer’s patients’ brains. Thus, drugs that could alleviate the symptoms are cholinergic agonists of various kinds, such as physostigmine, and various cholinomimetics, drugs that mimic acetylcholine. Many cholinomimetics are so-called nootropic drugs, compounds that may be able to improve learning, memory, and cognitive functions. Dopamine, another neurotransmitter in the brain, has been found to be involved with the hallucinations and delusions of schizophrenics, and dopamine antagonists are used as
antipsychotic drugs. Amphetamine is known to induce those psychotic symptoms; this type of drug promotes the release of dopamine.
Furthermore, a lack of dopamine activity has been linked to the symptoms of Parkinson’s disease, so anti-Parkinson’s drugs tend to be dopamine agonists. Depression has been found to be related to reduced activity of norepinephrine in the brain, so some antidepressants are norepinephrine agonists. Morphine is a well-known pain reducer; in the body, there are chemically similar compounds known as endorphins (from “endogenous morphine”). They are released by neurons within the spinal cord, resulting in a reduction of the release of the neurotransmitter (called substance P) related to pain signaling, thus suppressing pain. Arousal is known to be related to acetylcholine and norepinephrine in the brain; dreaming has also been related to norepinephrine. The action of the tranquilizer diazepam (Valium), the most commonly prescribed drug in the United States, is related to the activity of an inhibitory neurotransmitter, gamma-aminobutyric acid. Neuropsychopharmacology is the area of study that explores the relationships among neurophysiology, neuroanatomy, and pharmacology. Neurotransmission is an important key to discovering these relationships. Beyond the importance of such research efforts, however, it must also be remembered that behavior, both normal and abnormal, is inextricably related to the effects of synaptic transmission.
Discovering New Neurotransmitters
In the earliest years of the twentieth century, neurotransmission was thought to be solely electrical. The discovery of the synaptic cleft, however, made neuroscientists wonder whether an electrical current could jump a gap of this magnitude. The chemical hypothesis of neurotransmission was then proposed, although it was not until 1921 that convincing evidence of chemical transmission was obtained. Otto Loewi, a German physiologist, electrically stimulated the parasympathetic vagus nerve of a frog and recorded the effect on the frog’s heart. He then transferred the liquid from the stimulated heart to an unstimulated frog heart and observed that the recipient heart reacted as if it were stimulated. The effect of the vagal stimulation—decreasing the heart rate—was transferred to the unstimulated heart via the liquid from the stimulated heart. This transferral could only occur if the electrical stimulation of the vagus had resulted in the release of a chemical into the heart and this chemical was transferred to the new heart, thus inducing the same effect. Loewi called this substance Vagusstoff, since it was released from the vagus nerve. Later chemical analysis revealed the substance to be acetylcholine, the first neurotransmitter to be identified.
No fewer than fifty neurotransmitter substances have been identified, and researchers are still discovering new ones. To classify a substance as a neurotransmitter, a scientist needs to show that it fulfills a number of conditions. The substance (referred to as a putative neurotransmitter) should be found in the presynaptic terminals. Exogenous applications of the substance should mimic the effect of endogenously released substance when the presynaptic neurons are electrically stimulated. The drug effect should be the same as the effect of the exogenously applied substance and the same as the effect of the endogenously released transmitter substance. A mechanism must exist for the synthesis of the substance in the presynaptic neuron. A mechanism must also exist for the termination of the transmitter activity of the substance. As can be seen, it is not easy to identify and define a new neurotransmitter substance.
The United States Public Health Service proclaimed the 1990’s to be the decade of the brain. The synthesis of drugs that may be related to brain functions is still an area of intense research activity. Neuropsychopharmacological studies test the effects of various compounds; the new compounds are also used to test for specific neuronal bases of brain functions. New drugs not only increase the possibilities for controlling neuronal function but also reduce the undesirable side effects of drug therapy by making the effects specific to receptor subtypes. Better, more effective drugs will undoubtedly continue to be produced.
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