5-Hydroxytryptamine brain function

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. 

Stanford, S. C. (2001). 5-Hydroxytryptamine. In Neurotransmitters, Drugs and Brain Function, ed. R. A. Webster, pp. 187-209. Chichester John Wiley Sons. 

Sizer AR, Long SK, Roberts MHT A modulatory function of 5-hydroxytryptamine in the central nervous system, in Serotonin, CNS Receptors and Brain Function (Advances in the Biosciences, Vol 85). Edited by Bradley PB, Handley SL, Cooper SJ, et al. Oxford, England, Pergamon, 1992, pp 135-146 Skett P Biochemical basis of sex differences in drug metabolism. Pharmacol TTier 38 269-304, 1988... 

Tryptamine itself is found in all major centers of the brain. Its physiologic role in central nervous system (CNS) function, however, remains unclear. 5-Hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter in the CNS. The structural similarity of the tryptamine-related hallucinogens with 5-HT presumably forms the neurochemical basis for their action within the CNS. 

Enteric nerves control intestinal smooth muscle action and are connected to the brain by the autonomic nervous system. IBS is thought to result from dysregulation of this brain-gut axis. The enteric nervous system is composed of two gan-glionated plexuses that control gut innervation the submucous plexus (Meissner s plexus) and the myenteric plexus (Auerbach s plexus). The enteric nervous system and the central nervous system (CNS) are interconnected and interdependent. A number of neurochemicals mediate their function, including serotonin (5-hydroxytryptamine or 5-HT), acetylcholine, substance P, and nitric oxide, among others. 

Nygren, L. G., Fuxe, K., Jonsson, G., and Olson, L. (1974) Functional regeneration of 5-hydroxytryptamine nerve terminals in the rat spinal cord following 5,6-dihydroxytryptamine induced degeneration. Brain Res., 78 377-394. 

Green, A. R., and Grahame-Smith, D. G. (1976) Effects of drugs on the process regulating the functional activity of brain 5-hydroxytryptamine. Nature, 260 487-491. 

Ramirez-Latorre J, Yu CR, Qu X, Perin F, Karhn A, Role L (1996) Functional contributions of alpha5 subunit to neuronal acetylchohne receptor channels. Nature 380 347-351 Rasmussen BA, Perry DC (2006) An autoradiographic analysis of [ l]alpha-bungarotoxin binding in rat brain after chronic nicotine exposure. Neurosci Lett 404 9-14 Reuben M, Clarke PB (2000) Nicotine-evoked [ H]5-hydroxytryptamine release from rat striatal synaptosomes. Neuropharmacology 39 290-299... 

In a series of studies, Markou and her colleagues have sought to identify drugs that ameliorate the changes in brain reward function evoked by nicotine withdrawal (see Kenny and Markon 2001 for review). This review snmmarises the evidence that 5-hydroxytryptamine (5-HT) and, especially, 5-HTia receptors may play an important role in nicotine withdrawal, although the specific nature of the changes evoked... 

Rose JE, Levin ED (1991) Inter-relationships between conditioned and primary reinforcement in the maintenance of cigarette smoking. Br J Addict 86(5) 605-609 Rosecrans JA (1971) Elfects of nicotine on brain area 5-hydroxytryptamine function in male and female rats separated for differences of activity. Eur J Pharmacol 16(1) 123-127 Rosecrans JA (1972) Brain area nicotine levels in male and female rats with different levels of spontaneous activity. Neuropharmacology ll(6) 863-870 Rosecrans JA, Schechter MD (1972) Brain area nicotine levels in male and female rats of two strains. Arch Int Pharmacodyn Ther 196(l) 46-54 Saigusa T, Takada K, et al (1997) Dopamine efflux in the rat nucleus accumbens evoked by dopamine receptor stimulation in the entorhinal cortex is modulated by oestradiol and progesterone. Synapse 25(1) 37 3... 

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. 

Mechanism of Action An antihypertensive that depletes stores of catecholamines and 5-hydroxytryptamine in many organs, including the brain and adrenal medulla. Depression of sympathetic nerve function results in a decreased heart rate and a lowering of arterial blood pressure. Depletion of catecholamines and 5-hydrox-ytryptamine from the brain is thought to be the mechanism of the sedative and tran-quilizing properties. Therapeutic Effects Decreases blood pressure and heart rate sedation. 

Cabteta, T.M., and Battaglia, G. (1994) Delayed decreases in brain 5-hydroxytryptamine 2a/2c receptor density and function in male tat ptogeny following ptenatal fluoxetine./ Pharmacol Exp Ther 269 637-645. 

GOthert M, Duhrsen U (1979) Effects of 5-hydroxytryptamine and related compounds on the sympathetic nerves of the rabbit heart. Naunyn Schmiedebergs Arch Pharmacol 308 9-18 Gotti C, Zoli M, Clementi F (2006) Brain nicotinic acetylcholine receptors native subtypes and their relevance. Trends Pharmacol Sci 27 482-91 Grady SR, Meinerz NM, Cao J, Reynolds AM, Picciotto MR, Changeux JP, McIntosh JM, Marks MJ, Collins AC (2001) Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus a function mediated by a different nAChR than dopamine release from striatum. J Neurochem 76 258-68... 

Maswood N, Caldarola-Pastuszka M, Uphouse L. Functional integration among 5-hydroxytryptamine receptor families in the control of female rat sexual behavior. Brain Res 1998 802 98-103. 

The serotonergic system is involved in a large number of physiological functions, resulting from its widespread innervation of the brain. The axons of serotonergic neurons of the midbrain raphe nuclei reach almost every brain structure. Action potentials traveling along these axons release 5-hydroxytryptamine... 

In mammals 5-hydroxytryptamine is found in the brain, in the blood, and in the tissues of the stomach, intestines, and lungs its function in all these sites has not yet been fully elucidated. However, there is little doubt that it plays an extremely important role in the central nervous system, and, in particular, in the brain. The psychotomimetic activity of some drugs appears to be due to interference with the function of 5-hydroxytryptamine in the brain. It is also implicated in certain... 

Since they are tryptamine derivatives, the indolic hallucinogens are structurally related to the neurohumoral factor serotonin (5-hydroxytryptamine). Serotonin is widely distributed in warmblooded animals. It accumulates in the brain, where it plays a role in the biochemistry of nervous regulations. Consequently, it seems that certain tryptamine structures which occur so frequently in hallucinogens, as well as in the neurohormone serotonin, may be biochemically important in the metabolism of psychic functions. . . ... 

MAO catalyzes the oxidative deamination of catecholamines, 5-hydroxytryptamine (serotonin), and other monoamines, both primary such as NE, and secondary such as EP. It is one of several oxidase-type enzymes whose coenzyme is the flavin-adenine-dinucleotide (FAD) covalently bound as a prosthetic group (Fig. 9-3). The isoalloxazine ring system is viewed as the catalytically functional component of the enzyme. In a narrow view N-5 and C-4a is where the redox reaction takes place (i.e., +H+, +le or -H+, -le), although the whole chromophoric N-5-C-4a-C-4-N-3-C-2-N-l region undoubtedly participates. Figure 9-3 is a proposed structure of MAO isolated from pig brain (Salach et al., 1976).4... 

The time course of noradrenaline loss and recovery in the brain of reserpinized animals is identical with that of 5-hydroxytryptamine and the possibility has to be considered that the central actions of reserpine are attributable to noradrenaline deficiency. Carlsson is the most active protagonist of this view . It is rather more acceptable than the 5-hydroxytryptamine hypothesis on theoretical grounds, for it associates depletion of transmitter with impairment of synaptic function and it is consonant with the established peripheral actions of reserpine. It does, of course, assume that noradrenaline is a central transmitter substance. The evidence that this... 

Schizophrenia 20, 128 Serotonin (5-hydroxytryptamine) human brain 57 ff kidney function 73, 74, 80, 102 localization 4, 5, 11 metabolism 17, 18 microcirculation 83, 84, 86 occurrence 41 ff Parkinson s disease 62 pharmacology 67 ff production 3... 

Pharmacological evidence was obtained several years ago that indicated that tryptophan is decarboxylated to tryptamine by both animal and bacterial enzymes. More recent studies have failed to detect this reaction, but instead have shown decarboxylation to occur only after oxidation of the indole nucleus to yield 5-hydroxytryptophan. Decarboxylation of 5-hydroxytryptophan produces 5-hydroxytryptamine, serotonin, which has important, though incompletely defined functions in animal physiology. In some animal livers there is an enzyme that decarboxylates cysteic acid to taurine. Glutamic decarboxylase has been found in animal brain, where it is responsible for the formation of 7-aminobutyric acid. This product has been implicated in nervous function as an inhibitor of synaptic transmission. ... 

Ginsenosides markedly prolong the time of survival in normobaric hypoxia stress mice, and regenerate locomotory activity in mice. They possess anti-stress activities and show effects on neurotransmitters. The observed anti-heat stress effects of ginsenosides may be mediated by brain monoamines and the hypothalamus (HPA) system. Ginsenosides selectively modulate the circadian variations of brain 5-hydroxytryptamine (5-HT), 5-hydroxy-indole-3-acetic acid (5-HIAA), nor-epinedrine (NE) and dopamine (DA) levels, but as a function of the time of the light-dark cycle [79, 80]. 

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