5- Hydroxytryptamine system

Serotoninergic System. Figure 1 Graphical representation of the current classification of 5-hydroxytryptamine (5-HT) receptors. Receptor subtypes represented by shaded boxes and lowercase designate receptors that have not been demonstrated to definitively function in native systems. Abbreviations 3-5r cyclic adenosine monophosphate (cAMP) phospholipase C (PLC) negative (-ve) positive (+ve)... 

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. 

HT3 receptor. 5-Hydroxytryptamine receptor a receptor for serotonin (a neurotransmitter), which activates a variety of second messenger signaling systems and through them indirectly regulates the function of ion channels. 

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. 

In view of this neurotoxicity, we will review some data relevant to this process. First, we will review data showing that methamphetamine (METH), a prototypic psychomotor stimulant, which has been widely used for nonmedical purposes at doses often a good deal higher than therapeutie doses, is neurotoxic to dopamine (DA) and serotonin (5-hydroxytryptamine (5-HI)) systems. Second, we will examine the evidence that other substituted phenethylamines are also neurotoxic to certain transmitter systems. Last, we will examine the behavioral and pharmacological consequences of neurotoxicity that result from exposure to some of these amphetamine-related drugs. 

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. 

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). 

Green, A. R., and Grahame-Smith, D. G. (1976) (-)-Propranolol inhibits the behavioral responses of rats to increased 5-hydroxytryptamine in the central nervous system. Nature, 262 594-596. 

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... 

The use of HPLC to analyze biogenic amines and their acid metabolites is well documented. HPLC assays for classical biogenic amines such as norepinephrine (NE), epinephrine (E), dopamine (DA), and 5-hydroxytryptamine (5-HT, serotonin) and their acid metabolites are based on several physicochemical properties that include a catechol moiety (aryl 1,2-dihydroxy), basicity, easily oxidized nature, and/or native fluorescence characteristics (Anderson, 1985). Based on these characteristics, various types of detector systems can be employed to assay low concentrations of these analytes in various matrices such as plasma, urine, cerebrospinal fluid (CSE), tissue, and dialysate. 

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. 

Some rather important indole derivatives influence our everyday lives. One of the most common ones is tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1). None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter in the central nervous system. 

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... 

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... 

Serotonin (4.109, 5-hydroxytryptamine, 5-HT) is a central neurotransmitter that is also found peripherally in the intestinal mucosa and in blood platelets, where its role is incompletely elucidated it even occurs in plants such as bananas. Although there is an enormous literature on the biochemistry and pharmacology of serotonin, our knowledge of its biological role remains somewhat fragmented. The diverse physiological effects of 5-HT influence the cardiovascular system, the cerebrovascular system, the digestive... 

Neuronal systems that contain one of the monoamines—norepinephrine, dopamine, or 5-hydroxytryptamine (serotonin)— provide examples in this category. Certain other pathways emanating from the reticular formation and possibly some peptide-containing pathways also fall into this category. These systems differ in fundamental ways from the hierarchical systems, and the noradrenergic systems serve to illustrate the differences. 

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