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Panic Miracle System

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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 about 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 enterochro-maffin 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as a mechanism whereby the contraceptive pill, particularly the high oestrogen type of pill which has now largely been withdrawn, may predispose some women to depression by reducing the availability of free tryptophan for brain 5-HT synthesis.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 endogenous steroids, 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. Para-chloramphetamine 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 intersynaptic 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 some role in regulating the circadian rhythm, which may account for the occurrence of low plasma melatonin levels in depressed patients.

A summary of the major steps that lead to the synthesis of 5-HT, and of the minor pathway whereby the trace amine tryptamine is synthesized from tryptophan by the action of tryptophan hydroxylase, is shown in Figure 2.18.

Anatomical distribution of the central serotonergic system

Neurons containing 5-HT are restricted to clusters of cells around the midline of the pons and upper brainstem; this is known as the raphe area of the midbrain. In addition, according to studies of rat brain, cells containing 5-HT are located in the area postrema and in the caudal locus coeruleus, which forms an anatomical basis for a direct connection between the serotonergic and noradrenergic systems. The more caudal groups of cells in the raphe project largely to the medulla and the spinal cord, the latter projections being physiologically important in the regulation of pain perception at the level of the dorsal horn. Conversely, the more rostral cells of the dorsal and median raphe project to limbic structures such as the hippocampus and, in particular, to innervate extensively the cortex. Unlike the noradrenergic cortical projections, there does not appear to be an organized pattern of serotonergic terminals in the cortex. In general, it would appear that the noradrenergic and serotonergic systems are co-localized in most limbic areas of the brain, which may provide the anatomical basis for the major involvement of these transmitters in the affective disorders.

The distribution of the serotonergic system in the human brain is shown in Figure 2.19.

Amino acid neurotransmitters

Unlike for the ''classical'' neurotransmitters such as acetylcholine and noradrenaline, it has not been possible to map the distribution of the amino acid transmitters in the mammalian brain. The reason for this is that these transmitters are present in numerous metabolic pools in the brain and are not restricted to one particular type of neuron as occurs with the ''classical'' transmitters. As an example, glutamate is involved in peptide and protein synthesis, in the detoxification of ammonia in the brain (by forming glutamine), in intermediary metabolism, as a precursor of the inhibitory transmitter GABA and as an important excitatory transmitter in its own right. While the evidence in favour of the amino acids glutamate, aspartate, glycine and GABA as transmitters is good, it is not yet possible to describe their anatomical distribution in detail.

With regard to the possible role of these neurotransmitters in psychiatric and neurological diseases, there is growing evidence that

Figure 2.18. The major pathway leading to the synthesis and metabolism of 5-hydroxytryptamine (5-HT). Metabolism of tryptophan to tryptamine is a minor pathway which may be of functional importance following administration of a monoamine oxidase (MAO) inhibitor. Tryptamine is a trace amine. L-Aromatic amino acid decarboxylase is also known to decarboxylate dopa and therefore the term ''L-aromatic amino acid decarboxylase'' refers to both ''dopa decarboxylase"

and ''5-HTP decarboxylase".

Figure 2.18. The major pathway leading to the synthesis and metabolism of 5-hydroxytryptamine (5-HT). Metabolism of tryptophan to tryptamine is a minor pathway which may be of functional importance following administration of a monoamine oxidase (MAO) inhibitor. Tryptamine is a trace amine. L-Aromatic amino acid decarboxylase is also known to decarboxylate dopa and therefore the term ''L-aromatic amino acid decarboxylase'' refers to both ''dopa decarboxylase"

and ''5-HTP decarboxylase".

Figure 2.19. Anatomical distribution of the serotonergic pathways in human brain.

Figure 2.19. Anatomical distribution of the serotonergic pathways in human brain.

glutamate is causally involved in the brain damage that results from cerebral anoxia, for example following stroke, and possibly in epilepsy. Conversely, GABA deficiency has been implicated in anxiety states, epilepsy, Huntington's chorea and possibly parkinsonism. The roles of the excitatory amino acid aspartate and the inhibitory transmitter glycine in disease are unknown.

The principal amino acid transmitters and their metabolic inter-relationships are shown in Figure 2.20.

Glycine

Glycine is structurally the simplest amino acid. There is evidence that it acts as an inhibitory transmitter in the hindbrain and spinal cord. The seizures that occur in response to strychnine poisoning are attributable to the convulsant-blocking glycine receptors in the spinal cord. Recent evidence also suggests that glycine can modulate the action of the excitatory transmitter glutamate on the major excitatory amino acid receptor complex in the brain, the so-called N-methyl-D-aspartate (NMDA) receptor. As the density of NMDA receptor sites is high in the cortex, amygdala and basal ganglia, this might explain the relatively high concentration of glycine which also occurs in these brain regions.

Aspartate and glutamate

Aspartate and glutamate are the most abundant amino acids in the mammalian brain. While the precise role of aspartate in brain function is obscure, the importance of glutamate as an excitatory transmitter and as a precursor of GABA is well recognized. Despite the many roles which glutamate has been shown to play in intermediary metabolism and transmitter function, studies on the dentate gyrus of the hippocampal formation, where glutamate has been established as a transmitter, have shown that the synthesis of glutamate is regulated by feedback inhibition and by the concentration of its precursor glutamine. Thus the neuronal regulation of glutamate synthesis would appear to be similar to that of the ''classical'' transmitters. In the brain, there appears to be an inverse relationship between the concentration of glutamate and of GABA, apart from the context where both amino acids are present in low concentrations.

Figure 2.20. Metabolic inter-relationship between the amino acid transmitters glutamate, GABA and glycine. The diagram shows how glutamate and glycine synthesis are linked via the succinic acid component of the citric acid cycle. GABA, formed by the decarboxylation of glutamate, may also be metabolized to succinate via the ''GABA shunt''. Alpha-ketoglutarate acts as an intermediate between glutamate and glycine synthesis; the transfer of the — NH2 group from glycine to alpha-ketoglutarate leads to the synthesis of glutamate and glyoxylate.

Figure 2.20. Metabolic inter-relationship between the amino acid transmitters glutamate, GABA and glycine. The diagram shows how glutamate and glycine synthesis are linked via the succinic acid component of the citric acid cycle. GABA, formed by the decarboxylation of glutamate, may also be metabolized to succinate via the ''GABA shunt''. Alpha-ketoglutarate acts as an intermediate between glutamate and glycine synthesis; the transfer of the — NH2 group from glycine to alpha-ketoglutarate leads to the synthesis of glutamate and glyoxylate.

Figure 2.21. Diagrammatic representation of the distribution of GABA in the human brain.

Figure 2.21. Diagrammatic representation of the distribution of GABA in the human brain.

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Getting to Know Anxiety

Getting to Know Anxiety

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