catecholamines

Catecholamines comprise important neurotransmitters and hormones, of which the main ones are dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine). Other catecholamines occur in trace amounts in the body, and synthetic catecholamines are available; for example isoprenaline (isoproterenol) was previously employed for the relief of asthma, while α-methylDOPA reduces blood pressure. (They are all catechols (3, 4-dihydroxyphenyl-) attached to a side-chain which ends in an amine group (primary, -NH₂, or substituted e.g. -NHCH₃).)

Adrenaline is commonly associated with feelings of anxiety, stress, anger, and excitement (‘the adrenaline flowed’). The term ‘fight or flight’ is well-known in this context. While the overall picture is very complicated, it is clear that the catecholamines produced within the body play important roles in adapting the cardiovascular and other systems to an individual's changing needs in response to physical activity as well as to stressful or threatening events. They have these effects both by means of release as neurotransmitters from nerve endings of the sympathetic division of the autonomic nervous system or within the central nervous system, and also by discharge into the bloodstream from the adrenal medulla.

The different catecholamines, although closely related structurally, can have widely differing physiological and pharmacological properties; can only be explained if the systems with which they interact have finely evolved ways of distinguishing between them and of coupling them to different cellular events. The differences are not only between the effects of the different substances on similar cells, but between the effects of any one of the catecholamines on different cells, or on the same cells under different conditions.

Adrenaline and noradrenaline

In 1948, in an attempt to provide a framework for explaining the different effects of noradrenaline and adrenaline, Ahlquist proposed the presence of several membrane receptors (adrenoceptors), coupled to different responses in the various target organs and tissues. His system, refined and extended, has stood the test of time. The two basic types are called α- and β-adrenoceptors, with main subdivisions into α₁ and α₂ and β₁ and β₂ but even further sub-divisions exist. Two major dopamine receptors, D₁ and D₂, have been identified and, again, further receptors and subdivisions have been proposed. All these receptors mediate the actions of catecholamines on target cells by activating intracellular messengers. These trigger the appropriate mechanism controlling the response, which might be contraction or relaxation of smooth muscles (including those of blood vessels, bronchioles, or gut), or stimulation of enzyme action or of glandular secretion. It follows that the physiological and pharmacological actions of catecholamines can most effectively be described if their relative potencies on the different adrenoceptors, as well as the number and distribution of the adrenoceptors in the various organs and tissues, are known.

With few exceptions, the order of potency on α-adrenoceptors is noradrenaline, adrenaline, isoprenaline, while on the β-adrenoceptor, the order is reversed. Indeed, isoprenaline has virtually no effect on α-adrenoceptors. On the other hand, α-methylnoradrenaline is selective for α₂-adrenoceptors.

α₁-adrenoceptors are found on the cell membranes of smooth muscle, liver, salivary glands, and sweat glands, and on nerve cells in the central nervous system. When activated, they stimulate a sequence of chemical events of which the end result is mainly the release of calcium ions inside the cell, and this in turn mediates the final action. α₂-adrenoceptors are sited on nerve endings, both in those neurons that use noradrenaline as their neurotransmitter and other neurons that do not. They can also be found on smooth muscle where they mediate contraction. In the CNS, stimulation of α₂-adrenoceptors lowers blood pressure and causes sedation and even unconsciousness. The sequence of events that follows activation of α₂-adrenoceptors results in a reduction in the formation of cyclic adenosine monophosphate (cAMP) and this in turn mediates the ultimate effect.

β₁-adrenoceptors are the most important adrenoceptors in the heart, where they mediate increase in heart rate and force. They relax gut smooth muscle, cause breakdown of fat, and cause amylase secretion from salivary glands. On nerve endings, they increase transmitter release. β₂-adrenoceptors are on smooth muscle, including blood vessels, bronchioles, uterus, bladder, and the iris, where they mediate relaxation. They cause tremor in skeletal muscle (shivering) and the breakdown of glycogen in the liver to release glucose into the blood, and decrease histamine release from mast cells.

Dopamine

Dopamine exerts its actions via the D₁ and D₂ receptors, which reside very largely in the CNS. It has much less effect than either noradrenaline or adrenaline on either α- or β-adrenoceptors (because it lacks the β-hydroxyl group which these others have on the side chain). The vast majority of dopaminergic nerves (those which release dopamine as their neurotransmitter, at synapses with other neurons) are restricted to 3 pathways in the CNS, related to movement co-ordination, to thought, feeling, and behaviour, and to the control of hormone release from the anterior pituitary gland. There are related abnormalities: decrease in dopamine release in the first pathway (or the administration of drugs which block the action of dopamine) leads to disturbances of movement associated with Parkinson's disease; excess dopamine activity in the brain leads to stereotyped behaviours in experimental animals and may account for some of the symptoms of schizophrenia in man; dopamine, and drugs that mimic it, cause nausea and vomiting through an action on a trigger zone in the brain stem. Its action on the pituitary leads to reduced prolactin and increased growth hormone release. It causes vasodilatation of blood vessels in the kidney and mesentery through interaction with dopamine receptors, vasoconstriction elsewhere via α₁-adrenoceptors, and stimulation of the heart via β₁-adrenoceptors.

Endogenous catecholamines are synthesized in neurons and in the chromaffin cells of the adrenal medulla, and stored in intracellular vesicles. Dopamine is formed first from the aminoacid, tyrosine. Dopamine is the immediate precursor of noradrenaline, which is in turn the precursor of adrenaline. This full sequence takes place only in chromaffin tissue, where all three substances are made, and in a relatively small number of truly ‘adrenergic’ nerves in the CNS, which release adrenaline as their transmitter. Nearly all so-called ‘adrenergic neurons’ (comprising most of the final or ‘post-ganglionic’ sympathetic nerve supply to the various tissues) are, in reality, ‘noradrenergic’, because they release noradrenaline as their transmitter and are unable to synthesize adrenaline. Likewise, ‘dopaminergic’ neurons release dopamine and cannot make either noradrenaline or adrenaline.

The actions of catecholamines after their release are terminated by their re-uptake into the sympathetic nerve endings and into certain non-neuronal cells such as smooth muscle. After re-uptake in nerve cells they are broken down by the action of monoamine oxidase; this enzyme plays a vital role in controlling the concentrations of catecholamine transmitters while scavenging and destroying unwanted amines. Catecholamines taken up by cells other than neurons are also degraded by enzymes. The combined product of these actions on both noradrenaline and adrenaline is vanilmandelic acid, which appears in normal urine. Raised excretion of vanilmandelic acid can indicate the presence of a catecholamine-secreting tumour.

— B. A. Callingham

See also adrenal gland; autonomic nervous system; neurotransmitters.

A group of chemicals known as biogenic amines, which can act as neurotransmitters and hormones. They include adrenaline (epinephrine), dopamine, and noradrenaline (norepinephrine).

The principal catecholamines found in the mammalian nervous system are noradrenaline (norepinephrine), dopamine, and adrenaline (epinephrine). The adrenal medulla, an endocrine gland which receives innervation from the sympathetic nervous system, contains the largest quantities of catecholamines in the body. This tissue was used in pioneer studies to determine the biosynthetic pathway for the catecholamines. This is as follows: tyrosine → dihydroxyphenylalanine → dopamine → noradrenaline → adrenaline.

The ability of cells to synthesize catecholamines depends on the presence of enzymes which catalyse the conversion of tyrosine, taken up from the bloodstream, to dihydroxyphenylalanine, dopamine, noradrenaline, and adrenaline. Noradrenaline and adrenaline in the adrenal medulla function as hormones and are released into the bloodstream in response to activation of the input it receives from the sympathetic nervous system. This occurs during physiological responses to stressful stimuli such as sudden anger, fear, severe cold, or physical exercise.

In the peripheral nervous system, the postganglionic neurons of the sympathetic division of the autonomic nervous system synthesize and release noradrenaline as a neurotransmitter, thereby influencing the activity of smooth muscle cells in a wide variety of tissues. For example, they control the diameter of the pupil, the smooth muscle in blood vessels of the salivary glands (thus influencing glandular secretion), the rate of the heartbeat, the diameter of the coronary arteries, the diameter of bronchi in the lungs, the activity of smooth muscle in the bowel (thus influencing movement of intestinal contents), the smooth muscle activity in a variety of pelvic organs, and the diameter of small blood vessels and hence blood flow in large areas of skin and muscle throughout the body. These diverse tissues can thus be influenced by the sympathetic nervous system to respond in a coordinated fashion to stressful stimuli. The well-known cold sweaty hands, fast heartbeat, dilated pupils, and pale complexion produced by fear are explicable in terms of the known hormonal and neurotransmitter actions of the catecholamines.

The brain contains another and separate family of neurons using catecholamines as neurotransmitters. These contain adrenaline, noradrenaline, or dopamine. Adrenaline neurons are few in number and are located in the brain stem. They send their axons down into the spinal cord and into the hypothalamus, as well as to a region of the brain stem known as the nucleus of the tractus solitarius. There is evidence that adrenaline plays a role in this latter nucleus in the control of blood pressure. Abnormally high blood pressure is a common clinical problem, and it is therefore of interest that a genetically distinct strain of laboratory rat has been found in which there are abnormally high quantities of the enzyme that synthesizes adrenaline. These rats suffer from high blood pressure.

Noradrenaline neurons are scattered in small groups throughout the brain stem. The largest of these, the locus ceruleus, contains only a few thousand neurons, but they provide branching axons which together innervate a vast area of the brain and spinal cord. Furthermore, neurons may provide axons to innervate, for example, both cerebellum and cerebral cortex. Therefore these neurons may influence widely separate and functionally distinct brain areas simultaneously (see neuronal connectivity and brain function). Morphologically these neurons have many similarities to other parts of the brain-stem reticular formation, and make many functional contacts with other divisions of the reticular formation. All the evidence points to the fact that the synaptic actions (see synapses) of noradrenaline are relatively diffuse (or hormone-like) and act over a relatively slow time course of seconds (compared to a time course of milliseconds for acetylcholine), while the action of the transmitter is mediated by slow chemical changes rather than fast changes in ionic channels in the nerve-cell membrane. In most cases it seems that the action of the transmitter on single neurons is inhibitory, although it appears to operate without altering the responses of neurons to other specific input stimuli.

As would be expected from the very widespread distribution of noradrenaline fibres in the brain and spinal cord, they appear to influence a correspondingly large number of functions. There seems little doubt that they are involved in the regulation of general brain states such as arousal and sleep, and the coordination of the many brain functions appropriate to these states. It is of interest that drugs which appear to have clinical activity in alleviating depressive illness are able to act by altering the availability of noradrenaline at the receptor level. Noradrenaline fibres may also have a role to play in the establishment and selection of normal synaptic connections during development and in the recovery of function after damage to the nervous system.

The third main group of catecholamine neurons of the brain are those utilizing dopamine as transmitter. These neurons have been the subject of much research, because there are two common clinical conditions alleviated by drugs that interact with dopamine neurons — Parkinsonism and schizophrenia.

(Published 1987)

— O. T. Phillipson

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