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Chapter 6 organic acidsOrganic Acids
autonomic and pain signals.262 Formation of both serotonin and 5-HTP within the spinal cord have been shown to be stimulated by administration of 5-HTP, and the increase is enhanced in experimentally induced encephalomyelitis (EAE), an experimental model system for human multiple sclerosis.263 Spinal cord generation Figure 6.13 —.Formation.and.Clearance.
of 5-HIAA increases in the initial inflammatory phase The availability of tryptophan in serotonergic neurons of the disease and decreases after destruction of nerve determines their ability to sustain serotonin levels. fibers.264 Decreased serotonin reuptake by damaged neu- Anything that increases serotonin turnover, such as rons and disruption of the blood-brain barrier have been increased neuronal activity or drugs that block synaptic suggested as mechanistic explanations. Such rationale re-uptake cause increased rates of 5-hydroxyindoleacetate formation and higher concentrations of the catabolic allows understanding of how serotonin may enter the CNS from 5-HTP produced in the periphery.263 The in-flammatory phase in the more caudal regions of the spi-nal cord also results in marked elevation of quinolinate only those who show high variability in 5-HIAA excre- in rats with induced EAE.265 Quinolinate is discussed tion in overnight urine experience watery diarrhea.272 further in the next section. Tryptophan supplementation Cerebrospinal fluid 5-HIAA and HVA showed highly significant positive correlations with Alzheimer’s Carcinoid tumors composed of chromaffin tissue disease.273 These monoamine disturbances may be in can release large amounts of serotonin.268, 269 Urinary response to the pathophysiology of this disease. Experi- 5-HIAA has been recommended for diagnosis of some mental allergic neuritis also exhibits elevated serotonin types of carcinoid tumor cases.270 Investigations of the precursors, indicating that they may play a role in the pathogenesis of serotonin secretion and high 5-HIAA clinical course of this disorder.274 5-HIAA is also greatly excretion in carcinoid heart disease showed no associa- increased in the first attack of chronic relapsing allergic tion with transforming growth factor beta or fibroblast encephalomyelitis, indicating a potential explanation of growth factor.271 Among patients with carcinoid tumors, Table 6.8 — Relative Selectivity of New Antidepressants for Serotonin
Over Noradrenaline and Dopamine Uptake230
5-HIAA AND VMA
5-HIAA AND HVA
The values show the relative selectivity for serotonin reuptake versus either noradrenaline or dopamine. Citalopram, with a ratio of 1500:1, is highly selective for serotonin receptors, so it produces increased turnover of serotonin with corresponding tendency to deplete tryptophan pools with little effect on tyrosine demand for noradrenaline production. Amitriptyline, on the other hand, has a ratio near 1:1, so it tends to cause increases in both neurotransmitters, thus increasing the urinary concentrations of their catabolic products, 5-HIAA and VMA. For most of the drugs, the effects on dopamine relative to serotonin paral el those for noradrenaline. A notable exception is that a patient using clomipramine is unlikely to show elevated HVA along with the elevating effect on 5-HIAA. The data do not indicate the potencies for serotonin uptake. Thus, while citalopram is more selective than sertraline, it is a less potent serotonin reuptake inhibitor.
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