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High-dose pyridoxine as an 'anti-stress' strategy

MEDICAL HYPOTHESES 2000年第5期54卷 803-807页

作者： McCarty, MF Pantox Labs San Diego CA 92109 USA

Pyridoxine nutritional status has a significant and selective modulatory impact on central production of both serotonin and GABA - neurotransmitters which control depression, pain perception, and anxiety - owing to the fact that the decarboxylases which produce these neurotransmitters have a relatively low affinity for pyridoxal phosphate (PLP). Pyridoxine deficiency leads to increased sympathetic outflow and hypertension in rodents, possibly reflecting decreased central production of these neurotransmitters;conversely, supplemental pyridoxine lowers blood pressure in many animal models of hypertension, and there is preliminary evidence for antihypertensive activity in humans as well. Additionally physiological levels of PLP interact with glucocorticoid receptors to down-regulate their activity. Thus, high-dose pyridoxine, by amplifying tissue levels of PLP, may be expected to have a favorable impact on certain dysphoric mental states, while diminishing sympathetic output and acting peripherally to blunt the physiological impact of corticosteroids. In light of growing evidence that chronic dysphoria, particularly when accompanied by hopelessness or cynicism, has a major negative impact on morbidity and mortality from a wide range of disorders, high intakes of pyridoxine may have the potential to improve prognosis in many individuals. With respect to cardiovascular health, reduction of homocysteine levels should contribute to this benefit. These predictions are consistent with recent epidemiology correlating plasma PLP levels with risk for vascular events and overall survival. (C) 2000 Harcourt Publishers Ltd.

关键词：剂量效应关系药物吡多辛/投药和剂量吡多辛/治疗应用血清素/生物合成应激心理学/药物疗法应激心理学/病因学维生素B6缺乏/并发症维生素B6缺乏/药物疗法 γ氨基丁酸/生物合成动物人类

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Posttraining inactivation of excitatory afferent input to the locus coeruleus impairs retention in an inhibitory avoidance learning task

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NEUROBIOLOGY OF LEARNING AND MEMORY 2000年第2期73卷 127-140页

作者： Clayton, EC Williams, CL Univ Virginia Dept Psychol Charlottesville VA 22903 USA

These experiments examined whether the nucleus paragigantocellularis (PGi) contributes to memory storage processing via its ascending excitatory influence on locus coeruleus (LC) neuronal activity. Activation of the LC leads to memory enhancement and also results in a widespread release of norepinephrine in target structures, such as the amygdala and hippocampus. Infusion of norepinephrine into either structure also improves memory for several types of learned responses. Thus, the capacity for norepinephrine to modulate memory within limbic structures may be contingent upon the functional connections between PGi and the LC, To examine this hypothesis, male Sprague-Dawley rats were implanted with cannula aimed above PGI (Experiments 1 and 2) or 1.5 mm dorsal or medial to PGi (Experiment 3). Immediately following inhibitory avoidance training (0.45 mA, 0.5 s), phosphate-buffered saline, lidocaine (Experiment 1), or 12.5 or 25 nmol/0.5 mu l of the GABA agonist muscimol (Experiment 2) was infused into PGi. On a retention test given 48 h later, the latency to reenter the footshock compartment was significantly shorter for subjects given either lidocaine or 12.5 or 25.0 nmol of muscimol compared to controls. In Experiment 3, infusion of lidocaine or muscimol into areas 1.5 mm dorsal or medial to PGi did not significantly alter retention, indicating that the memory impairment observed in Experiments I and 2 was site specific and not due to the spread of drug to cell groups surrounding PGi. These findings suggest that PGi may serve a vital function in relaying biologically relevant information to forebrain structures involved in memory via its excitatory influence on the LC. (C) 2000 Academic Press.

关键词：麻醉药局部/投药和剂量回避学习/药物作用回避学习/生理学 GABA激动剂/投药和剂量抑制(心理学) 利多卡因/投药和剂量蓝斑/药物作用蓝斑/生理学记忆/药物作用记忆/生理学微量注射蝇蕈醇/投药和剂量神经网/药物作用神经网/生理学大鼠 Sprague-Dawley 菱脑/药物作用菱脑/生理学血清素/生物合成动物男(雄)性大鼠

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Competitive antagonism of the mouse 5-hydroxytryptamine₃ receptor by bisindolylmaleimide I, a "selective" protein kinase C inhibitor

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期290卷 76-82页

作者： Coultrap, SJ Sun, HW Tenner, TE Machu, TK Texas Tech Univ Hlth Sci Ctr Dept Pharmacol Lubbock TX 79430 USA

We examined the effects of several protein kinase C (PKC) inhibitors on the murine 5-hydroxytryptamine(3) (5-HT3) receptor to determine whether they acted directly on the receptor. The 5-HT-evoked currents in Xenopus laevis oocytes expressing the recombinant 5-HT3 receptor were measured with the two-electrode voltage-clamp technique. The PKC inhibitors bisindolylmaleimide I (BIM, GF109203x) and staurosporine, but not calphostin C or chelerythrine, decreased the 5-HT3 receptor-mediated currents when coapplied with 5-HT. BIM blocked 0.5 mu M 5-MT-elicited currents with an IC50 value of 7 nM, whereas in the presence of 5 mu M staurosporine, 42% inhibition of 0.5 mu M 5-HT-mediated currents was observed. Increasing concentrations of BIM resulted in a rightward shift of the 5-HT concentration-response curve, without altering efficacy. A Schild plot was generated, which had a slope of -1.01, suggesting competitive antagonism. The K-i value of BIM was determined to be 29 nM. To confirm competitive antagonism, a competitive binding assay was performed on Sf21 insect cells infected with the mouse 5-HT3 receptor cDNA in a baculovirus expression vector. BIM completely displaced binding of the selective 5-HT3 receptor antagonist [H-3]GR65630. BIM bound to the 5-HT3 receptor with a K-i value of 61 nM, which was slightly less potent than that of the selective 5-MT, receptor antagonist MDL72222 (27 nM). The PKC inhibitor BIM is a potent competitive antagonist at the 5-HT3 receptor.

关键词：生物碱类苯并菲啶类结合竞争性细胞膜/代谢 DNA/生物合成酶抑制剂/药理学吲哚类/拮抗剂和抑制剂吲哚类/药理学马来酰亚胺类/拮抗剂和抑制剂马来酰亚胺类/药理学萘类/药理学卵母细胞/代谢膜片钳术菲啶类/药理学蛋白激酶C/拮抗剂和抑制剂 RNA/生物合成受体血清素/生物合成受体血清素/药物作用受体血清素/遗传学受体血清素 5-HT3 血清素拮抗药/药理学星状孢子素/药理学爪蟾光滑动物小鼠

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Acute tryptophan depletion in healthy young women with a family history of major affective disorder

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PSYCHOLOGICAL MEDICINE 1999年第1期29卷 35-46页

作者： Ellenbogen, MA Young, SN Dean, P Palmour, RM Benkelfat, C McGill Univ Dept Psychiat Sch Dietet & Human Nutr Dept Biol Montreal PQ H3A 1A1 Canada McGill Univ Dept Human Genet Montreal PQ Canada

Background. Acute tryptophan depletion (ATD), a means of reducing brain serotonin synthesis, lowers mood in normal males with a multi-generational family history of major affective disorder (MAD) and in normal women devoid of any family history of psychiatric illness. As both a family history of MAD and female sex are factors predisposing to depression, the hypothesis that a mood lowering response to ATD may reflect a susceptibility to depression was further investigated in young women with an extensive, multi-generational family history of MAD. In addition, the temporal stability of mood change following repeated trials of ATD was also assessed in this study. Methods. To deplete tryptophan, a tryptophan deficient amino acid mixture was ingested on two separate occasions. The control treatment, administered on a third occasion, was a nutritionally balanced amino acid mixture containing tryptophan. Results. A marked lowering of plasma tryptophan (85-90%) was achieved by both depletions. In comparison to the balanced condition, family history positive (FH +) women showed no lowering of mood to either the first or second ATD (N = 13) and N = 12, respectively). Mood change between the two ATD trials (N = 13) exhibited poor temporal stability. Conclusions, These results may indicate that serotonin responsiveness is not an important characteristic of vulnerability to depression in these women. Alternately, these negative results may be due to the exclusion of a large number of FR + women who had already experienced an episode of depression, resulting in the selection of a. biased FH+ sample who are resistant to the mood lowering effects of ATD.

关键词：脑/代谢抑郁症/药物疗法抑郁症/遗传学抑郁症/心理学系谱血清素/生物合成性别因素色氨酸/血液色氨酸/缺乏色氨酸/治疗应用青少年成年人女(雌)性人类

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Acute effects of 3,4-methylenedioxymethamphetamine on brain serotonin synthesis in the dog studied by positron emission tomography

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NEUROCHEMISTRY INTERNATIONAL 1999年第1期34卷 33-40页

作者： Nishisawa, S Mzengeza, S Diksic, M McGill Univ Montreal Neurol Inst Dept Neurol & Neurosurg Montreal PQ H3A 2B4 Canada

The influence of an acute dose (2 mg/kg;i.v.;infused over 10 min) of 3,4-methylenedioxymethamphetamine (MDMA;Ecstasy) on the brain serotonin synthesis in the dog was assessed using alpha[C-11]methyl-L-tryptophan and positron emission tomography. The rate of serotonin synthesis measured 1 h after injection of MDMA was six times greater than the base line (before MDMA) synthesis. Five hours after the MDMA injection, serotonin synthesis was about one half that at the base line, and about one thirteenth of the synthesis at 1 h after MDMA. A large increase seen 1 h after MDMA probably relates to the large release of serotonin by MDMA and reflects an attempt of the serotonergic system to replenish released serotonin. This probably correlates with the mood changes reported by humans after MDMA intake. Decrease observed 5 h after MDMA, in part, probably relates to the inhibitory effects of the released serotonin, which could act on the activity of tryptophan hydroxylase directly or indirectly via other monoaminergic systems (e.g, dopaminergic). (C) 1999 Published by Elsevier Science Ltd. All rights reserved.

关键词：血脑屏障脑/药物作用脑/代谢动力学 N-甲基-3 4-亚甲二氧苯丙胺/药理学血清素/生物合成血清素类药/药理学体层摄影术发射型计算机色氨酸/血液动物狗

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Is α-methyl-L-tryptophan a good tracer for brain serotonin synthesis measurements, and does the lumped constant vary in different structures of the rat brain?

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JOURNAL OF NEUROCHEMISTRY 1999年第6期73卷 2621-2622页

作者： Diksic, M Leyton, M Benkelfat, C McGill Univ Dept Neurol & Neurosurg Montreal PQ Canada McGill Univ Dept Psychiat Montreal PQ Canada

Comments on an article about the use of alpha-methyl-L-tryptophan (alpha-MTrp) as tracer for measuring the rate of hydroxytryptamine synthesis in the brain. Overview of a study on alpha-MTrp; Information on the alpha-... 详细信息

关键词：算法脑/代谢脑/超微结构羟基化动力学模型生物学放射性示踪剂血清素/类似物和衍生物血清素/生物合成血清素/代谢色氨酸/类似物和衍生物色氨酸/药代动力学动物大鼠

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EFFECTS OF THE DIET ON BRAIN-FUNCTION

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ACTA ASTRONAUTICA 1981年第9-10期8卷 1035-1042页

作者： FERNSTROM, JD DepartmentofNutrition&FoodScience MassachusettsInstituteofTechnologyCambridge02139USA.

The rates of synthesis by brain neurons of the neurotransmitters serotonin, acetylcholine, and the catecholamines depend on the brain levels of the respective precursor molecules. Brain levels of each precursor are influenced by their blood concentration, and for the amino acid precursors, by the blood levels of other amino acids as well. Since diet readily alters blood concentrations of each of these precursors, it thereby also influences the brain formation of their neurotransmitter products.

关键词：乙酰胆碱/生物合成脑/代谢脑/生理学脑化学胆碱/代谢膳食神经元/代谢神经元/生理学去甲肾上腺素/生物合成血清素/生物合成色氨酸/代谢酪氨酸/代谢人类

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DOPAMINERGIC FUNCTION IN GILLES-DE-LA-TOURETTES SYNDROME, SYDENHAMS CHOREA AND TORSION DYSTONIA

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CLINICAL NEUROLOGY AND NEUROSURGERY 1976年第1期79卷 66-69页

作者： LAL, S ALLEN, J ETIENNE, P SOURKES, TL HUMPHREYS, P MCGILL UNIV DEPT PSYCHIATMONTREAL 101QUEBECCANADA MONTREAL GEN HOSP DEPT PSYCHIATMONTREAL H3G 1A4QUEBECCANADA MONTREAL CHILDRENS HOSP DEPT NEUROLMONTREAL H3H 1P3QUEBECCANADA

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CONTROL OF BRAIN MONOAMINE SYNTHESIS BY DIET AND PLASMA AMINO-ACIDS

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AMERICAN JOURNAL OF CLINICAL NUTRITION 1975年第6期28卷 638-647页

作者： WURTMAN, RJ FERNSTROM, JD MIT DEPT NUTR & FOOD SCILAB NEUROENDOCRINE REGULATIONCAMBRIDGEMA 02139

The rates at which monoaminergic neurons in rat brains synthesize their neurotransmitters depend on the availability of the amino acid precursors tryptophan (for serotonin) and tyrosine (for dopamine and norepinephrine). The administration of tryptophan, the injection of insulin, or the consumption of a single protein-free high-carbohydrate meal all elevate brain tryptophan levels and, soon thereafter, the levels of serotonin and its major metabolite 5-hydroxyindole acetic acid. The addition of protein to the meal suppresses the increases in brain tryptophan and serotonin, because protein contributes to plasma considerably larger amounts of the other neutral amino acids (e.g., leucine, phenylalanine) than of tryptophan, and these other amino acids compete with tryptophan for uptake into the brain. The elevation of brain tyrosine (by injection of the amino acid or consumption of a single 40% protein meal) accelerates brain catecholamine synthesis, as estimated by measuring brain dopa accumulation after decarboxylase inhibition, or brain catecholamine accumulation after inhibition of monoamine oxidase. These observations suggest that serotonin- and catecholamine-containing brain neurons are normally under specific dietary control.

关键词：氨基酸类/血液脑/代谢儿茶酚胺类/生物合成膳食膳食碳水化合物/投药和剂量膳食蛋白质类/投药和剂量多巴胺/生物合成羟基吲哚乙酸/代谢单胺氧化酶/代谢神经组织蛋白质类/代谢神经元/生理学去甲肾上腺素/生物合成蛋白质缺乏/代谢血清素/生物合成色氨酸/代谢酪氨酸/代谢动物大鼠

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