Serotonin and Metabolites

Theophylline, caffeine, aminophylline, theobromine, p-hydrocyethyltheophylline, phenylbutazone, hydro-chloro-thiazide, acetominophen Fluvoxamine and possible isomers Hydroquinone and ethers Serotonin and metabolites... 

Kema IP, de Vries EG, Muskiet FA. Clinical chemistry of serotonin and metabolites. J Chromatogr B Biomed Sci Appl 2000 747 33-48. 

Panholzer, T. J. Beyer, J. Lichtwald, K., Coupled-column liquid chromatographic analysis of catecholamines, serotonin, and metabolites in human urine, Clin. Chem. 1999, 45, 262-268... 

Serotonin and metabolites OT, fused silica etched with NH4HF2, — [116]... 

Mefford, I. N., 1981, Application of HPLC with electrochemical detection to neurochemical analysis measurement of catecholamines, serotonin, and metabolites in rat brain, /. Neurosci. Meth. 3 207-224. 

Fig. I Chromatogram of catecholamines, serotonin and some metabolites together with creatinine A) examination at X = 365 nm, B) examination at A. = 254 nm.

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

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. 

Pharmacology Venlafaxine and its active metabolite, 0-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. 

Mechanism of Action An antidepressant that appears to inhibit serotonin and norepinephrine reuptake at CNS neuronal presynaptic membranes is a less potent inhibitor of dopamine reuptake. Therapeutic Effect Relieves depression. Pharmacokinetics Well absorbed from the G1 tract. Protein binding greater than 90%. Extensively metabolized to active metabolites. Excreted primarily in urine and, to a lesser extent, in feces. Half-life 8-17 hr. 

Low serotonin and dopamine metabolite concentrations in cerebrospinal fluid from bulimic patients with frequent binge episodes. Arch Gen Psychiatry 49 132-138. 

The mechanism of deprenyl s action is unclear. In addition to enhancing dopaminergic activity in the brain by inhibiting dopamine degradation, deprenyl is metabolized into various stimulant metabolites. In spontaneously hyperactive rats used in an animal model of ADHD, chronic deprenyl administration improved im-pulsivity (but not hyperactivity or attention) along with altering levels of noradrenaline, dopamine, and serotonin and their metabolites (Boix et ah, 1998). 

As outlined previously, initial biological hypotheses of mood disorders were derived from the pharmacological actions of antidepressant drugs, which increase synaptic concentrations of noradrenaline (NA] and/or serotonin. Consequently, the biogenic amine hypothesis was formulated, but it lacks consistent proof that NA and/or serotonin release is indeed diminished. This failure is in part a result of the limited access to relevant brain areas. Measurements of NA and serotonin and their metabolites in blood, urine, and CSF... 

Serotonin and its metabolites are reduced in the cerebrospinal fluid of some depressive patients, which suggests reduced serotoninergic activity in the brain of these individuals. 

The sum of the concentration of venlafaxine and ODV is probably more important than their relative ratio. Thus, CYP 2D6 deficiency, which occurs in approximately 7% of Caucasians, has fewer clinical implications for venlafaxine than for drugs that are biotransformed by this isoenzyme to either centrally inactive metabolites (e.g., paroxetine) or metabolites that have a different pharmacological profile than the parent drug (e.g., TCAs). The increase in venlafaxine plasma levels is offset by a parallel decline in ODV levels such that the sum is the same. Nevertheless, a substantial inhibition of CYP 3A3/4 could result in a meaningful increase in both venlafaxine and ODV plasma levels, particularly in patients who are CYP 2D6 deficient. Such an increase would be expected to result in an increase in the incidence or severity of the known dose-dependent effects of venlafaxine mediated by its inhibition of the neuronal uptake pumps for serotonin and NE. 

Before the identification of 5-hydroxytryptamine (5-HT), it was known that when blood is allowed to clot, a vasoconstrictor (tonic) substance is released from the clot into the serum. This substance was called serotonin. Independent studies established the existence of a smooth muscle stimulant in intestinal mucosa. This was called enteramine. The synthesis of 5-hydroxytryptamine in 1951 permitted the identification of serotonin and enteramine as the same metabolite of 5-hydroxytryptophan. 

Hyland K, Surtees RAH, Heales SJR, Bowron A, et al (1993) Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 34 10-14... 

Few strong biological findings demonstrating lesions in specific psychiatric disorders Example discovery of changes in serotonin receptors and metabolites in depression, schizophrenia, and suicidal behavior... 

Sukul NC. 1990. Increase in serotonin and dopamine metabolites in mouse hypothalamus following oral administration of Agaricus muscarius 12, a homoeopathic drug. Sci cult 56 134-137. 

Fenfluramine, a racemic chemical more closely related to amphetamine than to serotonin, affects brain levels of serotonin and its metabolites at relatively low doses. It was introduced as an anorexigenic drug almost 20 years ago. Its d- isomer, J-fenfluramine (dexfenfluramine, Redux) was about twice as potent as fenfluramine. After several controlled clinical trials demonstrated that dexfenfluramine could help patients maintain weight loss for at least a year, it was quickly introduced into the market in the USA and became a best-selling drug overnight. 

TCDD was investigated. No changes were found in epinephrine and dopamine in the hypothalamus or in dopamine and its metabolites in the striatum. However, tryptophan (a precursor of serotonin) levels in plasma and brain were increased and this was paralleled by increases in brain serotonin and 5-hydroxyindolacetic acid (the major serotonin metabolite) (Rozman et al. 1991). Based on the results of these experiments, Rozman et al. (1991) proposed that decreased PEPCK activity decreases gluconeogenesis and leads to increased plasma concentrations of glycogenic amino acids, such as tryptophan. Increased tryptophan leads to increase in serotonin release in the brain and to appetite... 

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