5-HT
5-HT, together with noradrenaline, has long been implicated in the aetiology of depression. Indirect evidence has been obtained from the actions of drugs which can either precipitate or alleviate the symptoms of depression and from the analysis of body fluids from depressed patients. Recently, the development of novel anxiolytic drugs which appear to act as specific agonists for a subpopulation of 5-HT receptors (the 5-HT1A type) suggests that this amine may also play a role in anxiety. To add to the complexity of the role of 5-HT, there is evidence that impulsive behaviour as exhibited by patients with obsessive–compulsive disorders and bulimia may also involve an abnormality of the serotonergic system. Whether 5-HT is primarily involved in this disparate group of disorders or whether it functions to ‘‘fine tune’’ other neurotransmitters which are causally involved is presently unclear. 5-HT is an indoleamine transmitter which is synthesized within the nerve ending from the amino acid L-tryptophan. Tryptophan, which is obtained from dietary and endogenous sources, is unique among the amino acids concerned in neurotransmitter synthesis in that it is bout 85% bound to plasma proteins. This means that it is only the unbound portion that can be taken up by the brain and is therefore available for 5-HT synthesis. In the periphery, tryptophan may be metabolized in the liver via the kynurenine pathway, and it must be emphasized that the pathway that leads to the synthesis of 5-HT in the periphery (e.g. in platelets and the enterochromaffin cells of the gastrointestinal tract) or as a neurotransmitter in the brain is relatively minor. It is known that the activity of the kynurenine pathway, also known as the tryptophan pyrrolase pathway, in the liver can be increased by steroid hormones. Thus natural or synthetic glucocorticoids can induce an increase in the activity of this pathway and thereby increase the catabolism of plasma free tryptophan. Other steroids, such as the oestrogens used in the contraceptive pill, can also induce pyrrolase activity. This has been proposed as a mechanism whereby the contraceptive pill, particularly the high oestrogen type of pill which has now largely been withdrawn, may predispose some women to depression by reducing the availability of free tryptophan for brain 5-HT synthesis. Despite the plausible belief that the availability of plasma free tryptophan determines the rate of brain 5-HT synthesis, it now seems unlikely that such an important central transmitter would be in any way dependent on the vagaries of diet to sustain its synthesis! Nevertheless, changes in liver tryptophan pyrrolase activity, which may be brought about by endogenoussteroids, insulin, changes in diet and by the circadian rhythm, may play a secondary role in regulating brain 5-HT synthesis. Furthermore, there is evidence that a tryptophan-deficient diet can precipitate depression in depressed patients who are in remission. Thus when such patients are given a drink containing high concentrations of amino acids but which lacks tryptophan, a depressive episode rapidly occurs. Free tryptophan is transported into the brain and nerve terminal by an active transport system which it shares with tyrosine and a number of other essential amino acids. On entering the nerve terminal, tryptophan is hydroxylated by tryptophan hydroxylase, which is the rate-limiting step in the synthesis of 5-HT. Tryptophan hydroxylase is not bound in the nerve terminal and optimal activity of the enzyme is only achieved in the presence of molecular oxygen and a pteridine cofactor. Unlike tyrosine hydroxylase, tryptophan hydroxylase is not usually saturated by its substrate. This implies that if the brain concentration rises then the rate of 5-HT synthesis will also increase. Conversely, the rate of 5-HT synthesis will decrease following the administration of experimental drugs such as para-chlorophenylalanine, a synthetic amino acid which irreversibly inhibits the enzyme. Parachloramphetamine also inhibits the activity of this enzyme, but this experimental drug also increases 5-HT release and delays its reuptake thereby leading to the appearance of the so-called ‘‘serotonin syndrome’’, which in animals is associated with abnormal movements, body posture and temperature.
Following the synthesis of 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase, the enzyme aromatic amino acid decarboxylase (also known as 5-HTP or dopa decarboxylase) then decarboxylates the amino acid to 5-HT. L-Aromatic amino acid decarboxylase is approximately 60% bound in the nerve terminal and requires pyridoxal phosphate as an essential enzyme. There is evidence that the compartmentalization of 5-HT in the nerve terminal is important in regulating its synthesis. It appears that 5-HT is synthesized in excess of normal physiological requirements and that some of the amine which is not immediately transported into the storage vesicle is metabolized by intraneuronal monoamine oxidase. Another autoregulatory mechanism governing 5-HT synthesis relies on the rise in the intersynapti c concentration of the amine stimulating the autoreceptor of the nerve terminal.
5-HT is metabolized by the action of monoamine oxidase by a process of oxidative deamination to yield 5-hydroxyindoleacetic acid (5-HIAA). In the pineal gland, 5-HT is o-methylated to form melatonin. While the physiological importance of this transmitter in the regulation of the oestrus cycle in ferrets would appear to be established, its precise role in man is unknown. Nevertheless, it has been speculated that melatonin plays somerole in regulating the circadian rhythm, which may account for the occurrence of low plasma melatonin levels in depressed patients.
5-HT, together with noradrenaline, has long been implicated in the aetiology of depression. Indirect evidence has been obtained from the actions of drugs which can either precipitate or alleviate the symptoms of depression and from the analysis of body fluids from depressed patients. Recently, the development of novel anxiolytic drugs which appear to act as specific agonists for a subpopulation of 5-HT receptors (the 5-HT1A type) suggests that this amine may also play a role in anxiety. To add to the complexity of the role of 5-HT, there is evidence that impulsive behaviour as exhibited by patients with obsessive–compulsive disorders and bulimia may also involve an abnormality of the serotonergic system. Whether 5-HT is primarily involved in this disparate group of disorders or whether it functions to ‘‘fine tune’’ other neurotransmitters which are causally involved is presently unclear. 5-HT is an indoleamine transmitter which is synthesized within the nerve ending from the amino acid L-tryptophan. Tryptophan, which is obtained from dietary and endogenous sources, is unique among the amino acids concerned in neurotransmitter synthesis in that it is bout 85% bound to plasma proteins. This means that it is only the unbound portion that can be taken up by the brain and is therefore available for 5-HT synthesis. In the periphery, tryptophan may be metabolized in the liver via the kynurenine pathway, and it must be emphasized that the pathway that leads to the synthesis of 5-HT in the periphery (e.g. in platelets and the enterochromaffin cells of the gastrointestinal tract) or as a neurotransmitter in the brain is relatively minor. It is known that the activity of the kynurenine pathway, also known as the tryptophan pyrrolase pathway, in the liver can be increased by steroid hormones. Thus natural or synthetic glucocorticoids can induce an increase in the activity of this pathway and thereby increase the catabolism of plasma free tryptophan. Other steroids, such as the oestrogens used in the contraceptive pill, can also induce pyrrolase activity. This has been proposed as a mechanism whereby the contraceptive pill, particularly the high oestrogen type of pill which has now largely been withdrawn, may predispose some women to depression by reducing the availability of free tryptophan for brain 5-HT synthesis. Despite the plausible belief that the availability of plasma free tryptophan determines the rate of brain 5-HT synthesis, it now seems unlikely that such an important central transmitter would be in any way dependent on the vagaries of diet to sustain its synthesis! Nevertheless, changes in liver tryptophan pyrrolase activity, which may be brought about by endogenoussteroids, insulin, changes in diet and by the circadian rhythm, may play a secondary role in regulating brain 5-HT synthesis. Furthermore, there is evidence that a tryptophan-deficient diet can precipitate depression in depressed patients who are in remission. Thus when such patients are given a drink containing high concentrations of amino acids but which lacks tryptophan, a depressive episode rapidly occurs. Free tryptophan is transported into the brain and nerve terminal by an active transport system which it shares with tyrosine and a number of other essential amino acids. On entering the nerve terminal, tryptophan is hydroxylated by tryptophan hydroxylase, which is the rate-limiting step in the synthesis of 5-HT. Tryptophan hydroxylase is not bound in the nerve terminal and optimal activity of the enzyme is only achieved in the presence of molecular oxygen and a pteridine cofactor. Unlike tyrosine hydroxylase, tryptophan hydroxylase is not usually saturated by its substrate. This implies that if the brain concentration rises then the rate of 5-HT synthesis will also increase. Conversely, the rate of 5-HT synthesis will decrease following the administration of experimental drugs such as para-chlorophenylalanine, a synthetic amino acid which irreversibly inhibits the enzyme. Parachloramphetamine also inhibits the activity of this enzyme, but this experimental drug also increases 5-HT release and delays its reuptake thereby leading to the appearance of the so-called ‘‘serotonin syndrome’’, which in animals is associated with abnormal movements, body posture and temperature.
Following the synthesis of 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase, the enzyme aromatic amino acid decarboxylase (also known as 5-HTP or dopa decarboxylase) then decarboxylates the amino acid to 5-HT. L-Aromatic amino acid decarboxylase is approximately 60% bound in the nerve terminal and requires pyridoxal phosphate as an essential enzyme. There is evidence that the compartmentalization of 5-HT in the nerve terminal is important in regulating its synthesis. It appears that 5-HT is synthesized in excess of normal physiological requirements and that some of the amine which is not immediately transported into the storage vesicle is metabolized by intraneuronal monoamine oxidase. Another autoregulatory mechanism governing 5-HT synthesis relies on the rise in the intersynapti c concentration of the amine stimulating the autoreceptor of the nerve terminal.
5-HT is metabolized by the action of monoamine oxidase by a process of oxidative deamination to yield 5-hydroxyindoleacetic acid (5-HIAA). In the pineal gland, 5-HT is o-methylated to form melatonin. While the physiological importance of this transmitter in the regulation of the oestrus cycle in ferrets would appear to be established, its precise role in man is unknown. Nevertheless, it has been speculated that melatonin plays somerole in regulating the circadian rhythm, which may account for the occurrence of low plasma melatonin levels in depressed patients.
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