5-Hydroxytryptamine/noradrenaline

Belcher, G., Ryall, R. W., and Schaffner, R. (1978) The differential effects of 5-hydroxytryptamine, noradrenaline and raphe stimulation on nociceptive and non-nociceptive dorsal horn intemeurons in the cat. Brain Res., 151 529-531. 

Calapai G, Crupi A, Firenzuoli F, et al. Effects of Hypericum perforatum on levels of 5-hydroxytryptamine, noradrenaline and dopamine in the cortex, diencephalon and brainstem of the rat. J Pharm Pharmacol 1999 51 723-728. 

Some of the physiological and biochemical actions of the barbiturates are similar to those exhibited by chlorpromazine and the other tranquillizers. Thus, the ascending reticular system is inhibited and there is evidence that barbiturates both stimulate and inhibit the hypothalamus. Their greater hypnotic action is probably due to the fact that, like all potential anaesthetics, they cause a general depression of the central nervous system. Like chlorpromazine, some barbiturates uncouple oxidative phosphorylation in vitro (p. 301). On the other hand, the barbiturates do not exert any antagonism in vitro towards histamine, 5-hydroxytryptamine, noradrenaline or acetylcholine nor is their adininistration accompanied by signs of extra-pyramidal stimulation. 

Preoccupation with the conflicting claims of noradrenaline and 5-hydroxy-tryptamine should not be allowed to obscure the fact that reserpine has actions on other neurohumoral systems. It has already been pointed out that reserpine causes a loss of GABA and dopamine from the brain. The case of dopamine is particularly important since compounds such as a-MT and a-MMT reduce the dopamine content of brain, though not to the same extent as the noradrenaline content. Everett and Wiegand measured the 5-hydroxytryptamine, noradrenaline and dopamine content of brain during... 

There is 5-hydroxytryptamine in weever fish venom besides protein. It is believed that local pain is attributed to the presence of 5-hydroxytryptamine (27). Other small compounds such as histamine, adrenaline, and noradrenaline are also present in the weever fish (28). 

After an overview of neurotransmitter systems and function and a consideration of which substances can be classified as neurotransmitters, section A deals with their release, effects on neuronal excitability and receptor interaction. The synaptic physiology and pharmacology and possible brain function of each neurotransmitter is then covered in some detail (section B). Special attention is given to acetylcholine, glutamate, GABA, noradrenaline, dopamine, 5-hydroxytryptamine and the peptides but the purines, histamine, steroids and nitric oxide are not forgotten and there is a brief overview of appropriate basic pharmacology. 

A link between the central monoamines, 5-hydroxytryptamine (5-HT) and noradrenaline, and depression was forged some 40 years ago and arose from clinical experience with the drugs, reserpine and iproniazid. At that time, reserpine was used as an... 

Neurochemical theories for the affective disorders propose that there is a link between dysfunctional monoaminergic synapses within the central nervous system (CNS) and mood problems. The original focus was the neurotransmitter noradrenaline, or NA (note noradrenaline is called norepinephrine, or NE, in American texts). Schildkraut (1965) suggested that depression was associated with an absolute or relative deficiency of NA, while mania was associated with a functional excess of NA. Subsequently, another monoamine neurotransmitter 5-hydroxytryptamine (5-HT), or serotonin, was put forward in a rival indoleamine theory (Chapter 2). However, it was soon recognised that both proposals could be reconciled with the available clinical biochemical and pharmacological evidence (Luchins, 1976 Green and Costain, 1979). 

Biogenic amines are of great interest to researchers because of their potential roles in several psychiatric and neurological disorders. They include dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT, serotonin), histamine, and trace amines such as 2-phenylethylamine (PEA), tyramine, octopamine, phenylethanolamine, and tryptamine (Coutts and Baker, 1982). Although GC assays for DA, NA, and 5-HT are available, HPLC analysis with electrochemical detection has for many years now been the method of choice for analysis of these neurotransmitter amines. 

This condition is cansed by a deficiency of one or more of the monoamine nenrotransmitters in the brain (e.g. noradrenaline, dopamine, 5-hydroxytryptamine). One means of increasing the concentration of the neurotransmitters is to inhibit one of the enzymes that degrade the neurotransmitter in the brain. For the monoamines, a key degradative enzyme is monoamine oxidase, which catalyses the reaction... 

The pathways for synthesis of the monoamine neurotransmitters are not, at least in some neurones, saturated with precursor amino acids (tyrosine for formation of noradrenaline plus dopamine tryptophan for formation of 5-hydroxytryptamine (serotonin)). Marked increases in the blood level of these amino acids can increase their concentrations in neurones which can influence the concentration of the respective neurotransmitters in some neurones in the brain. This may result in changes in behaviour. 

Type II neurotransmitters These are slow-acting neurotransmitters, including acetylcholine, noradrenaline, adrenaline, dopamine and 5-hydroxytryptamine (Figure 14.6). 

Certain foods can trigger a migraine attack by effects on neurotransmitter release or metabolism in the brain. For example, a number of foods contain tryptamine which is known to cause release of other amines (dopamine, noradrenaline and 5-hydroxytryptamine) from both nerve terminals and platelets. This release could initiate the sequence of events that results in the migraine attack. Elimination of such foods from the diet can decrease the number of headaches. Compounds that discourage platelet aggregation (e.g. aspirin) may prevent such attacks. 

There is now evidence that the mammalian central nervous system contains several dozen neurotransmitters such as acetylcholine, noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), together with many more co-transmitters, which are mainly small peptides such as met-enkephalin and neuromodulators such as the prostaglandins. It is well established that any one nerve cell may be influenced by more than one of these transmitters at any time. If, for example, the inhibitory amino acids (GABA or glycine) activate a cell membrane then the activity of the membrane will be depressed, whereas if the excitatory amino acid glutamate activates the nerve membrane, activity will be increased. The final response of the nerve cell that receives all this information will thus depend on the balance between the various stimuli that impinge upon it. 

The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in depressed patients. Whereas the overall psycho-physiological effects of noradrenaline in the CNS appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood. It is not surprising therefore to find that the serotonergic system is abnormal in depression. This is indicated by a reduction in the main 5-HT metabolite, 5-hydroxy indole acetic acid (5-HIAA), in the cerebrospinal fluid of severely depressed patients and a reduction in 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims. The 5-HT receptor function also appears to be abnormal in depression. This is indicated by an increase in the density of cortical 5-HT2a receptors in the brains of suicide victims and also on the platelet membrane of depressed patients. Platelets may be considered as accessible models of the nerve terminal. 

The various hypotheses that have been advanced regarding the biochemical cause of mania mainly centre on the idea that it is due to a relative excess of noradrenaline, and possibly dopamine, with deficits also arising in the availability of 5-hydroxytryptamine (5-HT) and acetylcholine. This simplistic view forms the basis of the amine theory of affective disorders... 

Baker GB, Reynolds GP Biogenic amines and their metabolites in Alzheimer s disease noradrenaline, 5-hydroxytryptamine and 5-hydroxy indole-3-acetic acid depleted in hippocampus but not in substantia innominata. Neurosci Lett 100 335-339, 1989... 

Nicholson AN, Pascoe PA 5-Hydroxytryptamine and noradrenaline uptake inhibition studies on sleep in man. Neuropharmacology 25 1079-1083, 1986 Nicholson AN, Pascoe PA Studies on the modulation of the sleep-wakefulness continuum in man by fluoxetine, a 5-HT uptake inhibitor. Neuropharmacology 27 597-602, 1988... 

It is an alkaloid obtained from an African plant Yohimbehe. Chemically it is an indolealkylamine related to reserpine. It has selective blocking property with short duration of action and also blocks 5-hydroxytryptamine receptors. It produces increase in heart rate and blood pressure due to increase in noradrenaline release. It does not have any role in clinical practice. 

It is an alkaloid obtained from the roots of Ramvolfia serpentina. It is known to deplete the catecholamines - adrenaline, noradrenaline and dopamine from the various sites in the body. It also depletes 5-hydroxytryptamine (serotonin). 

At present, in addition to acetylcholine, glutamate, and y-aminobutyrate (GABA), glycine, noradrenaline (norepinephrine), and dopamine and 5-hydroxytryptamine (serotonin) are regarded as established transmitters. Other probable (putative) or possible candidate transmitters are also known. Aspartate, taurine, and a large number of peptides (Tables 30-1,30-4) are under consideration. 

Quercetin also inhibited rat aortic contractions induced by noradrenaline, 5-hydroxytryptamine, and caffeine in Ca2+ -free media [110]. PMA enhanced this transient contraction elicited by noradrenaline, an effect that was abolished by quercetin. Furthermore, quercetin or the PKC inhibitor staurosporine, had no effect on 45Ca2+ efflux under resting conditions or when stimulated by noradrenaline. So, the inhibitory effects of quercetin on phasic contractile response induced by receptor agonists in... 

Fig. 1. Occurrence of H3 receptors inhibiting release of acetylcholine, of amino acid and monoamine neurotransmitters in the mammalian CNS in vitro. The schematic drawing represents a midsagittal section of the human brain three areas with a more lateral position are shown by broken line (substantia nigra and part of the hippocampus and of the striatum). For each of the six regions of the CNS (subregions given in brackets), in which H3 heteroreceptors have been identified, the neurotransmitter(s) and the species are indicated. The superscripts refer to the numbers of the papers as listed under References. Own unpublished data suggest that an H3 receptor-mediated inhibition of noradrenaline release also occurs in the human cerebral cortex and hippocampus and in the guinea-pig cerebral cortex. Note that a presynaptic location has not been verified for each of the H3 heteroreceptors or has been even excluded (for details, see Table 1). Abbreviations ACh, acetylcholine DA, dopamine GABA, y-aminobutyric acid Glu, glutamate 5-HT, 5-hydroxytryptamine, serotonin NA, noradrenaline...

Yokoo H, Goldstein M, Meller E (1988) Receptor reserve at striatal dopamine receptors modulating the release of [3H] dopamine. Eur J Pharmacol 155 323-7 Yokoyama H, Onodera K, Maeyama K, Sakurai E, Iinuma K, Leurs R, Timmerman H, Watanabe T (1994) Clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, inhibits electrically induced convulsions in mice. Eur J Pharmacol 260 23-8 Yoshimoto R, Miyamoto Y, Shimamura K, Ishihara A, Takahashi K, Kotani H, Chen AS, Chen HY, Macneil DJ, Kanatani A, Tokita S (2006) Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus. Proc Natl Acad Sci USA, in press Young CS, Mason R, Hill SJ (1988) Studies on the mechanism of histamine-induced release of noradrenaline and 5-hydroxytryptamine from slices of rat cerebral cortex. Biochem Pharmacol 37 2799-2805... 

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