5-Hydroxytryptamine neurones

Boden PR, Woodruff GN, Pinnock RD Pharmacology of a cholecystokinin receptor on 5-hydroxytryptamine neurons in dorsal raphe of the rat. Br J Pharmacol 102 635-638, 1991... 

Jansson A, Tinner B, Steinbusch HWM, Agnati LF, Fuxe K. On the relationship of 5-hydroxytryptamine neurons to 5-hydroxytryptamine 2A receptor-immunoreactive neuronal processes in the brain stem of rats. A double immunolabelling analysis. NeuroReport 1998 9 2505-2511. 

Varga V, Szekely AD, Csillag A, Sharp T, Hajos M. Evidence for a role of GABA intemeurones in the cortical modulation of rnidbrain 5-hydroxytryptamine neurones. Neuroscience 2001 106 783-792. 

Fuxe K, Famebo LO, Hamberger B, Ogren SO. On the in vivo and in vitro actions of fenfluramine and its derivatives on central monoamine neurons, especially 5-hydroxytryptamine neurons, and their relation to the anorectic activity of fenfluramine. Postgrad Med J 1975 51(Suppl 1) 35—45. 

Carlsson, A., Fuxe, K., Ungerstedt, U. The effect of imipramine on central 5-hydroxytryptamine neurons. J. Pharm. Pharmacol. 1968, 20, 150-151. 

Marsden, C. a., 1979, Functional aspects of 5-hydroxytryptamine neurones. Application of electrochemical monitoring in vivo, Trends Neurosci. 2 230-234. 

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. 

Ross, S.B. Ogren, S.O. and Renyi, L. Antagonism of the acute and longterm biochemical effects of 4-chloroamphetamine on the 5-HT neurons in rat brain by inhibitors of the 5-hydroxytryptamine uptake. Acta Pharmacol Toxicol [Copenh] 39 456-476, 1976. 

Hajos, M. and Sharp, T., A 5-hydroxytryptamine lesion markedly reduces the incidence of burst-firing dorsal raphe neurones in the rat, Neurosci. Lett. 204(3), 161-164, 1996. 

Randic, M., and Yu, H. H. (1976) Effects of 5-hydroxytryptamine and bradykinin in cat dorsal horn neurones activated by noxious stimuli. Brain Res., 111 197-203. 

Bramwell, G. J., and Gonye, T. (1976) Responses of midbrain neurons to microiontophoretically applied 5-hydroxytryptamine Comparison with the response to intravenously administered lysergic acid diethylamide. Neuropharmacology, 15 456-461. 

Binds to DNA and prevents separation of the helical strands Affects neuronal transmissions Binds to opiate receptors and blocks pain pathway Acts as central nervous system depressant Inhibits Na/K/ATPase, increases intracellular calcium, and increases ventricular contractibility Blocks the actions of histamine on Hi receptor Blocks ai-adrenergic receptor, resulting in decreased blood pressure Inhibits reuptake of 5-hydroxytryptamine (serotonin) into central nervous system neurons Inhibits cyclooxygenase, inhibition of inflammatory mediators Inhibits replication of viruses or tumor cells Inhibits HIV reverse transcriptase and DNA polymerase Antagonizes histamine effects... 

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... 

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. 

This hypothesis, similarly, proposes that physical activity increases tryptophan transport into the presynaptic neurone, where it is used to synthesise 5-hydroxytryptamine. Hence, when the nerve is stimulated, more 5-hydroxytryptamine is released into the synapse and, if this is another inhibitory transmitter in the motor control pathway, it will inhibit contraction (Figure 13.28). This is one of several effects of 5-hydroxytryptamine in the brain which are probably achieved via different receptors on different neurones. All three hypotheses are summarised in Figure 13.29. 

Figure 13.28 A possible mechanism by which increased levels of tryptophan and/or tyrosine can occur in neurones and lead to fatigue. The mechanism proposes that physical activity increases the entry of tryptophan or tyrosine into the neurones which increases the concentration of the neurotransmitters, 5-hydroxy-tryptamine or dopamine, respectively. The neurotransmitters are present in vesicles in the presynaptic terminal (Chapter 14). (The pathways for the formation of 5-hydroxytryptamine and dopamine are described in Chapter 14.) This enhances the amount release into the synapses which decreases the excitation of 5-hydroxytryptamine or dopamine neurones in the motor control pathway. It is assumed that they are inhibitory neurotransmitters, they will reduce electrical activity in the motor control pathway and hence nervous stimulation of muscle fibres. This results in fatigue. Mechanisms by which physical activity might result in increased entry of these amino acids into the brain are presented in Appendix 13.5.

Figure 14.12 Various physiological conditions that are modified by 5-hydroxytryptamine, probably due to different receptors acting on different neurones for the neurotransmitter. The physiological significance of 5-hydroxytryptamine on mood is discussed below, its role in fatigue is discussed in Chapter 13 (See Figures 13.29 and 13.30). For its role in appetite, see Appendix 15.4.

It should be possible to treat the disease by increasing the concentration of the neurotransmitter in the synaptic cleft. There are, in principle, three ways in which this could be achieved, (i) Neurotransmitter synthesis could be increased, (ii) The rate of exocytosis could be increased, (iii) Removal of neurotransmitter from the synapse could be inhibited. Drugs that affect process (iii) have been developed. The tricyclic antidepressants and the specific serotonin (5-hydroxytryptamine) reuptake inhibitors (abbreviated to SSRIs) inhibit uptake of the neurotransmitter into the presynaptic on postsynaptic neurone. The most prescribed SSRI is fluoxetine (Prozac). 

It is currently in vogue as a drug that staves off fatigue, induces euphoria and reduces inhibitions. Although sudden death has been attributed to it, this is probably due to dehydration and hyperthermia. Long-term use may result in damage to the neurones in the brain that use 5-hydroxytryptamine as a neurotransmitter. 

Kirby LG, Chou-Green JM, Davis K, Lucki I (1997) The effects of different stressors on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Brain Res 760 218-230 Kirby LG, Rice KC, Valentino RJ (2000) Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus. Neuropsychopharmacology 22 148-162 Kozicz T, Yanaihara H, Arimura A (1998) Distribution of urocortin-like immunoreactivity in the central nervous system of the rat. J Comp Neurol 391 1-10 Lavicky J, Dunn AJ (1993) Corticotropin-releasing factor stimulates catecholamine release in hypothalamus and prefrontal cortex in freely moving rats as assessedby microdialysis. J Neurochem 60 602-612... 

Reserpine also interferes with the neuronal storage of a variety of central transmitter amines such that significant depletion of norepinephrine, dopamine, and 5-hydroxytryptamine (serotonin) occurs. This central transmitter depletion is responsible for the sedation and other CNS side effects associated with reserpine therapy. The depletion of brain amines also may contribute to the antihypertensive effects of reserpine. 

Hydroxytryptamine (5-HT), dopamine, and norepinephrine play important roles as central neurotrans-mitters in the process of erection. Still other substances or hormones, such as endorphins, oxytocin, vasopressin, adrenocorticotropic hormone (ACTH) and related peptides, and prolactin, appear to participate in the complex and coordinated process of penile erection. Central nonadrenergic neurons also may influence male sexual behavior. 

PHARMACOLOGICAL ACTIVITIES AND CLINICAL TRIALS 5-Hydroxytryptamine inhibition. Ethanol (80%) extract of the dried stem hark, in cell culture at a dose of 10 pg/mL, inhibited the uptake of serotonin (5HT) in rat brainstem neurons L... 

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