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Neurotransmitters of the Brain: Serotonin Noradrenaline (Norepinephrine), and Dopamine.

As the study of the brain continues to probe for answers to the questions concerning the mind, so the need to understand neurotransmitters and their receptors becomes increasingly important. Probably all brain functions are modulated through receptor site activity, including memory and other cognitive processes. Receptor sites are the targets for new generations of mind-altering drugs that promise relief from the symptoms of many brain disorders. The receptor is also the site for the destructive action of the addictive drugs.

Direct receptors are known as ionotropic because they are linked to ion channels, pores in the postsynaptic membrane that allow passage of ions when opened. They are either excitatory (e.g., [Na.sup.+] channels) or inhibitory (e.g., Cl- channels) and are rapid in action, operating in milliseconds.[1] Indirect receptors are referred to as metabotropic because they affect metabolic processes in the cell body beyond the synapse and take longer to have an effect, from whole seconds to perhaps hours. These activate G-proteins on the inner surface of the post-synaptic membrane, and G-proteins are linked to a "secondary messenger" (the neurotransmitter being the "primary messenger"), which activates enzymes within the cell cytoplasm. These enzymes have a wide range of cellular activities affecting metabolic processes, ionic diffusion through pores, and even gene expression.[1] Autoreceptors on the presynaptic membrane, or even the presynaptic cell body, are often indirect and regulate transmitter release.

Two major categories of neurotransmitters exist: the peptides and the amines. In addition, two other compounds, nitric oxide and carbon monoxide, have more recently been found to have neurotransmitter-like properties. Each transmitter has multiple classes of receptors with different functions, and each year more of these receptors are identified. There are several dozen known neurotransmitters--serotonin, noradrenaline, and dopamine being amongst the better known and more interesting--with a wide diversity of function. There are almost certainly more neurotransmitters to discover and more information to be learned about those we know already.

Serotonin

Serotonin (5-hydroxytryptamine, or 5HT) is important in mood, behavior, movement, pain appreciation, sexual activity, appetite, endocrine secretions, cardiac functions, and the sleep-wake cycle. Most of the brain's serotonin is found in the nine raphe nuclei strong out along the midline of the pons and medulla, parts of the brain stem (Fig 1). From here, a wide pattern of fibers extends to many parts of the brain, including the cerebral cortex and the limbic areas. These fibers form part of the "diffuse modulatory systems."[1,3] Serotonin is also produced within the pathway from the medulla to the hypothalamus, which conveys the stimulus for breast feeding. Activation of this pathway blocks the hypothalamic dopamine inhibition of prolactin, which can then be released from the anterior pituitary gland and stimulate breast milk production. Some serotonin is converted to melatonin in the pineal gland, which has neural connections with the retina and therefore responds to light intensity.[7] Melatonin is produced 5 to 10 times more in the dark than in the light and induces sleep. Seasonal affective disorder (SAD) occurs where lower light levels in winter cause disturbance of the serotonin and melatonin levels and may lead to depression, which can often be treated with exposure to light. Excess serotonin may be associated with anxiety and obsessive-compulsive states, and possibly eating disorders like anorexia and bulimia, which could be variations of a fear-related compulsion. Serotonin is also implicated in several other psychiatric and brain disorders, particularly depression, where there seems to be an imbalance with noradrenaline.[2,6] Some forms of epilepsy may also be associated with low serotonin levels.[5]

[Figure 1 ILLUSTRATION OMITTED]

Synthesis and Degradation of Serotonin

Serotonin is produced from the dietary amino acid tryptophan, which is moved across the blood brain barrier into the neuron by the large neutral amino acid transporter (LNAA). LNAA also moves other amino acids, notably, tyrosine, valine, leucine, and isoleucine, across the blood brain barrier. Tryptophan must compete with these for transportation into the brain. Therefore, the amount of tryptophan transported is dependent on both its concentration and the concentration of the other amino acids in the blood. Inside the neuron, the enzyme tryptophan hydroxylase (TRPH) converts tryptophan to 5-hydroxytryptophan. TRPH requires a number of other substances to function, notably oxygen and iron ([Fe.sup.++]). 5-Hydroxytryptophan is the substrate for another enzyme called aromatic amino acid decarboxylase (AAAD), which converts 5-hydroxytryptophan to serotonin. Vitamin [B.sub.6] (pyridoxine) is essential for the production of pyridoxal phosphate (PLP), which acts as a catalytic co factor to AAAD. Thus, vitamin [B.sub.6] is important in serotonin production. A lack of this vitamin in the diet causes neurological symptoms such as nervousness and irritability, peripheral neuropathy, and depression. Pyridoxine deficiency can be the cause of some seizures in children. Some drugs (e.g., isoniazid) are antagonistic to vitamin [B.sub.6], and supplements of the vitamin may be required when these drags are in use. Vitamin [B.sub.6] supplementation is unlikely to raise serotonin levels to above normal but will ensure normal levels are maintained. The metabolite, or waste product, of serotonin is produced by the enzymes monoamine oxidase (MAO) and aldehyde oxidase, which together catabolize serotonin to the waste metabolite 5-hydroxy indole acetic acid (5-HIAA), which is excreted via the cerebrospinal fluid (CSF) and the blood.[7]

Serotonin Receptors

Seven 5HT receptor classes with subtypes are so far known. Class [5HT.sub.1] (subtypes [5HT.sub.1A] to [5HT.sub.1F]) are all activators of the secondary messenger, cyclic AMP (cAMP). The enzymes involved and mechanism of action can be found under dopamine receptors and are illustrated in Fig 2. Class [5HT.sub.1A] is both an autoreceptor on the neuronal cell body and a postsynaptic membrane receptor that reduces adenylyl cyclase activity. [5HT.sub.1B] and [5HT.sub.1D] may be autoreceptors on the presynaptic membrane as well postsynaptic receptors and have the same inhibitory function on adenylyl cyclase. Subclass [5HT.sub.1C] and the class [5HT.sub.2] all act on phospholipase C. Class [5HT.sub.2] (subtypes [5HT.sub.2A] to [5HT.sub.2C]) are all postsynaptic receptors and activators of secondary messengers. Class [5HT.sub.3] is a postsynaptic receptor, activation of which opens calcium ion ([Ca.sup.2+]) channels. Classes [5HT.sub.4], [5HT.sub.6], and [5HT.sub.7] are all postsynaptic receptors that activate the secondary messenger cAMP, which causes stimulation of cellular enzymes. Class [5HT.sub.5] (subtypes [5HT.sub.5A] and [5HT.sub.5B]) are postsynaptic receptors, the function of which is not fully known.

[Figure 2 ILLUSTRATION OMITTED]

The understanding of these receptor types permits the introduction of drugs that bind to the various receptors, causing either a blocking (antagonist) or a stimulation (agonist) of the receptor. The treatment of migraine is a good example. Migraine headaches may be caused by excess blood to the brain due to neurogenically induced vasodilation. Because serotonin is a powerful vasoconstrictor, a lack of serotonin may be involved in the cause of some migraines. The modern treatment of migraines sometimes involves a serotonin agonist (e.g., sumatriptan), which acts in the same way as serotonin on the [5HT.sub.1] receptor in the brain to reduce blood flow.[4]

Noradrenaline

Noradrenaline (Fig 3) is a catecholamine neurotransmitter of arousal, enhancing the level of activity within the whole person. As such, it is most active during the day. Concentrations of noradrenaline occur in the locus ceruleus, a nucleus of the medulla, which is involved in anxiety, learning, and pleasure (i.e., psychological arousal). From here, a pattern of pathways passes out to many brain areas, similar to serotonin. This is another of the "diffuse modulatory systems."[1,3] The arousal effect of noradrenaline may be caused by the inhibitory action of the transmitter on a postsynaptic inhibitory neuron (i.e., inhibiting the inhibitor) or disinhibition.

[Figure 3 ILLUSTRATION OMITTED]

Lack of the neurotransmitter, or its imbalance with serotonin, may be the cause of unipolar or bipolar depressive psychosis, and specific antidepressant drugs target noradrenaline activity at the synapse.[2] In epilepsy, a lack of noradrenaline intensifies the frequency and duration of seizures, while noradrenaline release during a seizure appears to limit its spread and duration.[5]

Synthesis and Degradation of Noradranaline

Noradrenaline is produced from the dietary amino acid tyrosine. Tyrosine is converted first to dopa (dihydroxyphenylalanine) by tyrosine hydroxylase. Dopa is converted to noradrenaline by two enzymes, first to dopamine by dopa decarboxylase, then to noradrenaline by dopamine-beta-hydroxylase. Tyrosine competes with other amino acids (as previously mentioned) for transportation across the blood brain barrier into the central nervous system.

Degradation is similar to dopamine, using the enzyme catechol-0-methyl transferase (COMT), mono-amine oxidase (MAO), and enzymes called reductases. The result is the end product 4-hydroxy-3-methoxy-phenyl ethyl glycol (MHPG), which is excreted in the urine.[7]

Noradrenaline Receptors

Adrenergic receptors (i.e., those that respond to noradrenaline) occur both as synaptic autoreceptors and as postsynaptic receptors. The known adrenergic receptors are [Alpha]1, [Alpha]2, [Beta]1, and [Beta]2. They are all metabotropic, having a long-term action by activating intracellular enzymes.[7] The [Alpha]1 receptor activates the cellular enzyme phospholipase C (PLC), which affects changes in cell metabolism, including enzyme activity, gene expression, and protein synthesis. Most noradrenaline autoreceptors are of the [Alpha]2 type, which are associated with inhibition of another enzyme, adenylyl cyclase via the inhibitory [G.sub.i] protein, reducing cAMP production. They also cause an increase in [K.sup.+] and decrease in [Ca.sup.2+] permeability into the cell. The [Beta]1 receptor increases adenylyl cyclase activity, which increases cAMP production. Noradrenaline postsynaptic receptors are mostly [Beta]2 receptors, which increase cAMP, but in some cases this may have a poorly understood inhibitory effect on action potentials, possibly disinhibition.

Clinically, knowledge of the adrenergic receptors permits the use of drugs that bind specifically to them. Beta-blocker drugs (i.e., antagonists of the [Beta]-receptors) are used to reduce the effects of the sympathetic nervous system on various organs like the heart. Agonists of the adrenergic receptor act to augment the sympathetic nervous system, which produces noradrenaline at the terminal synapse. An example is the bronchodilator, salbutamol (albuterol), which increases the sympathetic activity on the bronchus. Drugs can be used to increase noradrenaline levels as a treatment of depression (e.g., the noradrenaline selective reuptake inhibitors).[2]

Dopamine

Dopamine (Fig 4) is a catecholamine neurotransmitter found in concentrations in the pathway existing from the substantia nigra to the corpus striatum (or neostriatum, the nigrostriatal pathway). It is also in the pathways from the ventral tegmental area of the brain stem to both the frontal cortex (mesocortical pathway) and nucleus accumbens of the limbic system (mesolimbic pathway).[3] The term mesostriatal system has been used by some authors to combine the nigrostriatal and mesolimbic pathways.[6] Dopamine is mostly an inhibitory neurotransmitter. For example, in the nigrostriatal pathway dopamine causes inhibition of excessive muscle tone. A lack of dopamine in this pathway is seen in Parkinson's disease with a marked increase in muscle tone. Dopamine in the latter two pathways causes arousal of the brain and of the whole individual. From the hypothalamus, dopamine inhibits the release of prolactin from the anterior pituitary gland, a system deactivated by breast feeding.

[Figure 4 ILLUSTRATION OMITTED]

Synthesis and Degradation of Dopamine

Dopamine is derived from the dietary amino acid tyrosine, and synthesis is via the same pathway as for noradrenaline. After use, some dopamine is taken back into the presynaptic bulb, but catabolism takes place both in the synaptic cleft and the bulb. The enzyme catechol-0-methyl transferase (COMT) partially inactivates the molecule that can be repackaged in the vesicles or degraded further. Mitochondrial-bound monoamine oxidase (MAO) and other oxidases or reductases further degrade the molecule completing deactivation. The end product is homovanillic acid (HVA, 4-hydroxy-3-methoxy-phenyl acetate), which is excreted via the cerebrospinal fluid (CSF).[7]

Dopamine Receptors

Several species of dopamine receptors have been found, [D.sub.1] to [D.sub.5], but [D.sub.1] and [D.sub.2] are the best known. [D.sub.1] is a G-protein-coupled metabotropic receptor that increases activity of the enzymes adenylyl cyclase and phospholipase C. Adenylyl cyclase converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). Cyclic AMP activates another enzyme called protein kinase A. This enzyme causes phosphorylation of cellular proteins (i.e., transferring phosphate [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] from ATP to other proteins like ion channels, G-proteins, enzymes, and receptors), slightly changing their shape and activity.[7] Phospholipase C hydrolyzes membrane phospholipid to form other secondary messengers. These cause the release or uptake of [Ca.sup.2+] within the cell cytosol, which may regulate rhythmic responses within these neurons. [D.sub.1] receptors are found in most of the dopaminergic pathways including the nigrostriatal pathway (within the basal ganglia). The [D.sub.2] receptor is G-protein coupled and decreases the activity of the enzyme adenylyl cyclase. The [D.sub.2]-linked G-protein regulates [K.sup.+] ion channels, increasing the [K.sup.+] input leading to hyperpolarization of the postsynaptic membrane. The [D.sub.2]-1inked G-proteins also regulate [Ca.sup.2+] channels, reducing [Ca.sup.2+] input to the cell. [D.sub.2] receptors are found in most of the dopaminergic systems (e.g., in the nigrostriatal pathway).[7] In the mesolimbic system, excess [D.sub.2] receptor stimulation has been thought to produce psychotic symptoms akin to schizophrenia and may offer some insight into this mentally disabling disease. The balance of activity between [D.sub.1] and [D.sub.2] is thought to be very important in the regulation of neuronal activity, and this concept of balance may be found to extend to the remaining three receptors as well.

[D.sub.3], [D.sub.4], and [D.sub.5] receptors are now known to exist. They also are G-protein coupled receptor systems. [D.sub.3] is a variant of [D.sub.2]; it is an autoreceptor more sensitive to dopamine than [D.sub.2].

Dopamine Autoreceptors

Dopamine autoreceptors are present at the mesostriatal neuron terminals that control dopamine synthesis and release, and on the cell body that controls the impulse firing rate. Autoreceptors also are found at the mesocortical neuron terminals that control dopamine release, but only those projecting to the piriform cortex (part of the limbic system) have termination autoreceptors that control dopamine synthesis.

Summary

Serotonin and noradrenaline strongly influence mental behavior patterns, while dopamine is involved in movement. These three substances are therefore fundamental to normal brain function. For this reason they have been the center of neuroscientific study for many years. In the process of this study, new understanding has been gained of the neurochemistry of several important mental health disorders, especially depression and schizophrenia, as well as epilepsy. Such knowledge offers new opportunities for advancements in neuropharmacology, for example, the development of new drugs specific to certain receptor types that will provide relief of symptoms for many sufferers.

Acknowledgments

I would like to extend my gratitude to Janet Vickers and other members of the Division of Applied Biological Sciences of City University, London, for their comments on this article, and to Shelley Welsman and Rachel Beadle of the Audio Visual Department of St. Bartholomew School at City University, London, for their professional assistance with the figures.

References

[1.] Bear MF, Connors BW, Paradiso MA: Neuroscience: Exploring the Brain. Williams and Wilkins, 1996.

[2.] Blows WT: The neuro-biology of antidepressants. J Neurosci Nurs 2000; 32(3): 177-180.

[3.] Haines DE: Neuroanatomy: An Atlas of Structures, Sections and Systems. Williams and Wilkins, 1995.

[4.] Hickey JV: The Clinical Practice of Neurological and Neurosurgical Nursing. Lippincott, 1997.

[5.] Johnson MV: Neurotransmitters and epilepsy. In: The Treatment of Epilepsy: Principles and Practice, 2nd ed, Wyllie E (editor). Williams and Wilkins, 1996.

[6.] Strange PG: Brain Biochemistry and Brain Disorders. Oxford University Press, 1992.

[7.] Wilde GC, Benzel EC: Essentials of Neurochemistry. Jones and Bartlett, 1994.

Questions or comments about this article may be directed to: William T. Blows, PhD BSc (Hons) RMN RNG RNT OstJ, Division of Applied Biological Sciences, St. Bartholomew School of Nursing and Midwifery, City University, 20 Bartholomew Close, London EC1A 7QN, England. He is a lecturer at the St. Bartholomew School of Nursing and Midwifery.
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Author:Blows, William T.
Publication:Journal of Neuroscience Nursing
Geographic Code:1USA
Date:Aug 1, 2000
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