RESUMEN
BACKGROUND: Dieting in healthy women results in a decrease in the availability of tryptophan (TRP), the amino-acid precursor of serotonin (5-HT), for brain 5-HT synthesis. This is associated with increases in the prolactin response to 5-HT drug challenge suggesting a 'supersensitivity' of 5-HT neuroendocrine responses. The aim of the study was to assess whether increased TRP intake during dieting would prevent the changes in TRP availability and 5-HT neuroendocrine function. METHOD: Fifty female subjects underwent a 1000 kcal daily diet for 3 weeks. In the final week of the diet subjects were randomly allocated to receive either nutritionally-sourced TRP (1.8 g daily) or placebo in a double-blind, parallel group, design. RESULTS: TRP supplementation failed to modify the dieting-induced reduction in fasting TRP availability to the brain. However, in contrast to placebo-treated subjects, subjects receiving additional TRP did not show enhanced prolactin responses to intravenous TRP challenge. CONCLUSIONS: The decrease in TRP availability produced by dieting may be due to increased TRP metabolism rather than decreased TRP intake. While TRP treatment did not increase fasting TRP availability it may have modified the effect of dieting on brain 5-HT function. Further studies will be needed to see if this effect of TRP has consequences for the effectiveness of dieting as means of weight control.
Asunto(s)
Dieta Reductora/efectos adversos , Triptófano/administración & dosificación , Triptófano/deficiencia , Administración Oral , Adolescente , Adulto , Encéfalo/fisiopatología , Método Doble Ciego , Ingestión de Energía/fisiología , Femenino , Humanos , Polvos , Prolactina/sangre , Serotonina/fisiología , Triptófano/sangreRESUMEN
Elemental chromium (Cr) is an essential micronutrient. It is required for optimal insulin activity and normal carbohydrate and lipid metabolism. Tri-valent chromium (Cr3+) is recommended for the treatment of diabetes and obesity. There is evidence that Cr3+ may have antidepressant properties, possibly by enhancement of monoamine function through its ability to increase amino acid transport to the brain. The aim of the present study was to investigate further the possible effects of Cr3+ treatment on peripheral amino acid availability and brain monoamine function in the rat. We undertook three studies in rats. The first was a time-course study in which animals were administered single doses of 50 mg/kg of Cr3+ picolinate and the second a dose-response study in which animals were given either 20 or 50 mg/kg Cr3+ picolinate versus vehicle alone via the intra-peritoneal route. In the third, animals were fed a diet containing Cr3+ picolinate (100 mg/kg) or a similar control diet for two weeks and were then sacrificed. Blood was sampled and brains were removed for later analysis. Results from the Cr3+ time-course study defined an optimal time for sampling of two hours after dosing. Results from the second study showed dose-related responses to Cr3+ treatment for a number of measured biochemical parameters including serum corticosterone. In the sub-chronic treatment study Cr3+ significantly increased serum free tryptophan (TRP), non-esterified free fatty acids (NEFFAs), corticosterone, together with brain TRP, serotonin (5-hydroxytryptamine, 5-HT), noradrenaline (NA) and pineal melatonin. From other studies in our laboratory we have shown that Cr3+ treatment can modify brain 5-HT function, perhaps by altering the sensitivity of central 5-HT2A receptors. The peripheral effect of Cr3+ picolinate treatments and their consequential central effect on increased serotonergic and noradrenergic function may suggest that Cr3+ could have some antidepressant-like actions. Future studies to confirm this are to be done.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Catecolaminas/metabolismo , Corticosterona/metabolismo , Norepinefrina/metabolismo , Ácidos Picolínicos/farmacología , Triptófano/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Colorimetría , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Masculino , Melatonina/análisis , Norepinefrina/sangre , Ácidos Picolínicos/administración & dosificación , Glándula Pineal/química , Ratas , Ratas Sprague-Dawley , Triptófano/sangreRESUMEN
RATIONALE: The serotonin precursor tryptophan (TRP) has been widely used as a nutritional supplement and antidepressant. Recently, however, the use of TRP has been severely restricted due to its association with the eosinophilic myalgic syndrome, an autoimmune disorder probably caused by ingestion of a contaminant produced in certain TRP manufacturing processes. OBJECTIVES: To determine the bioavailability of a nutritional source of TRP obtained from milk protein and to assess whether administration of this material produced neuroendocrine and neuropsychological effects consistent with increased brain serotonin activity. METHODS: We studied 24 healthy subjects who ingested approximately 1.8 g of nutritionally-sourced TRP or placebo in a double-blind, parallel group, design. We carried out venous sampling for amino acid and hormone estimation and performed a test of emotional processing using a facial expression recognition task. RESULTS: The nutritionally-sourced TRP caused a substantial increase in the availability of TRP in plasma. Relative to placebo the TRP material produced some evidence of an increase in plasma cortisol, and enhanced the perception of fearful and happy facial expressions. CONCLUSIONS: A nutritional source of TRP increased the availability of TRP for brain serotonin synthesis and produced endocrine and neuropsychological changes consistent with increased brain serotonin function. The effect of TRP on emotional processing may be relevant to its reported activity in primate studies of social behaviour.
Asunto(s)
Expresión Facial , Miedo , Triptófano/administración & dosificación , Triptófano/farmacología , Adulto , Disponibilidad Biológica , Dieta , Método Doble Ciego , Femenino , Hormona de Crecimiento Humana/agonistas , Hormona de Crecimiento Humana/metabolismo , Humanos , Hidrocortisona/agonistas , Hidrocortisona/metabolismo , Persona de Mediana Edad , Prolactina/agonistas , Prolactina/metabolismo , Serotonina/biosíntesis , Serotonina/farmacología , Triptófano/farmacocinéticaRESUMEN
RATIONALE: Recent case series suggest that chromium picolinate in doses of 400 microg daily may have antidepressant properties, perhaps through increasing the peripheral availability of tryptophan for brain serotonin (5-HT) synthesis. OBJECTIVES: To determine the effects of chromium treatment on plasma tryptophan availability and on brain 5-HT function in human and animal models. METHODS: We studied the effects of short-term chromium supplementation on plasma concentrations of tryptophan and other large neutral amino acids. Brain 5-HT function was assessed by measuring the corticosterone/cortisol response to the 5-HT precursor, 5-hydroxytryptophan (5-HTP), a response believed to be mediated via indirect activation of 5-HT(2A) receptors. RESULTS: In rats, chromium increased peripheral and central tryptophan availability and elevated brain 5-HT content. Changes in peripheral tryptophan availability were not seen in humans but in both rats and humans, chromium lowered the cortisol response to challenge with 5-HTP. CONCLUSIONS: Chromium can modify brain 5-HT function in humans and animals, perhaps by altering the sensitivity of central 5-HT(2A) receptors.
Asunto(s)
Cromo/farmacología , Receptores de Serotonina/metabolismo , Adulto , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Corticosterona/sangre , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Serotonina/metabolismo , Método Simple Ciego , Triptófano/sangreRESUMEN
A novel and highly sensitive method has been developed for the determination of catecholamines [noradrenaline (NA), dopamine (DA), serotonin (5-HT) and their metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA)] in brain tissue. The method uses isocratic reversed-phase HPLC with amperometric end-point detection. The calibration curve was linear over the range 10-150 pg on-column. The assay limits of detection for NA, DA, 5-HT, 5-HIAA and HVA were 3.8, 3.8, 6.8, 5 and 7.5 pg on-column, respectively. The mean inter- and intra-assay relative standard deviations (RSDs) over the range of the standard curve were less than 5%. The absolute recoveries averaged 99.1%, 99.5%, 97.7%, 99.5% and 98.8% for NA, DA, 5-HT, 5-HIAA and HVA, respectively.
Asunto(s)
Química Encefálica , Catecolaminas/análisis , Cromatografía Líquida de Alta Presión/métodos , Animales , Electroquímica , Ratas , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Venlafaxine, oxydesmethylvenlafaxine and an internal standard (paroxetine) were extracted from plasma by a solid-phase extraction technique. Chromatography was performed using isocratic reversed-phase high-performance liquid chromatography (HPLC) with coulometric endpoint detection. The standard curves were linear over the range 0-200 ng/ml for both venlafaxine and oxydesmethylvenlafaxine in plasma. The mean inter- and intra-assay coefficients of variation over the range of the standard curves were less than 10%. The absolute recovery averaged 74% for venlafaxine and 67% for oxydesmethylvenlafaxine. The sensitivity was 0.5 ng for both the analytes. Plasma profiles of the analytes following oral administration of venlafaxine, are presented.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Ciclohexanoles/sangre , Administración Oral , Ciclohexanoles/farmacocinética , Ciclohexanoles/normas , Succinato de Desvenlafaxina , Humanos , Paroxetina/análisis , Paroxetina/normas , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Clorhidrato de VenlafaxinaRESUMEN
The prolactin responses to the serotonin (5-HT) releasing agent d-fenfluramine (30 mg orally) were studied in 11 male normal volunteers after administration of hydrocortisone (20 mg orally, twice daily for 10 days) using a double-blind, placebo-controlled, cross-over design. While hydrocortisone treatment significantly elevated 24-h urinary cortisol excretion, it did not lower the prolactin response to d-fenfluramine. Plasma levels of d-fenfluramine and d-norfenfluramine were not altered by hydrocortisone treatment. These findings show that following 10 days administration of hydrocortisone, the prolactin responses to d-fenfluramine are not changed.
Asunto(s)
Antiinflamatorios/farmacología , Fenfluramina/farmacología , Hidrocortisona/farmacología , Prolactina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adulto , Humanos , MasculinoRESUMEN
Animal experimental studies suggest that the therapeutic effect of selective serotonin re-uptake inhibitors (SSRIs) may involve neuroadaptive changes in pre- and post-synaptic serotonin1A (5-HT1A) receptors. We used the endocrine and hypothermic responses to the 5-HT1A receptor agonist, gepirone (20 mg orally), to assess 5-HT1A receptor sensitivity in 37 healthy male volunteers who were studied before and following random double-blind, allocation to treatment with paroxetine, nefazodone or placebo for 17 days. Following antidepressant drug treatment, hypothermic responses to gepirone were markedly decreased by paroxetine but only slightly diminished by nefazodone. Paroxetine also lowered the growth hormone and cortisol responses to gepirone. There was no change in either hypothermic or endocrine response following placebo treatment. Our results suggest that paroxetine treatment produces a striking attenuation of measures of both pre- and post-synaptic 5-HT1A receptor function. Nefazodone appears to decrease the sensitivity of 5-HT1A autoreceptors to some extent and this effect may contribute to its antidepressant activity.
Asunto(s)
Antidepresivos de Segunda Generación/farmacología , Paroxetina/farmacología , Pirimidinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Triazoles/farmacología , Adulto , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Método Doble Ciego , Humanos , Hidrocortisona/sangre , Hipotermia/inducido químicamente , Hipotermia/fisiopatología , Masculino , Persona de Mediana Edad , Piperazinas , Receptores de Serotonina/fisiología , Receptores de Serotonina 5-HT1 , Serotonina/metabolismoRESUMEN
Sumatriptan succinate (the analyte) and naloxone (the internal standard) were extracted from plasma with a solid-phase extraction technique. Chromatography and detection were performed by isocratic reversed-phase high-performance liquid chromatography with coulometric end-point detection. The standard curve was linear over the range 0-100 ng/ml of sumatriptan succinate in plasma. The reproducibility (as defined by the coefficient of variation, C.V.) over the range of the standard curve was 4.9-7.3%. The recovery averaged 83%. The sensitivity was 0.25 ng of sumatriptan on column (allowing a concentration of 0.5 ng/ml to be determined from a 1-ml plasma sample volume). Plasma profiles of the analyte following subcutaneous (s.c.) administration in eight normal male volunteers, are presented.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Agonistas de Receptores de Serotonina/sangre , Sumatriptán/sangre , Cromatografía Líquida de Alta Presión/estadística & datos numéricos , Humanos , Masculino , Naloxona , Sensibilidad y Especificidad , Sumatriptán/administración & dosificaciónRESUMEN
Naloxone, the analyte and the internal standard, sumatriptan, are extracted from plasma using solid-phase extraction columns. Chromatography and detection are performed using isocratic reversed-phase high-performance liquid chromatography (HPLC) with coulometric end-point detection. The standard curve was linear over the range 0-50 ng/ml of naloxone in plasma. The reproducibility, the coefficient of variation (C.V.) of the method over the range of the standard curve was 6.2-11.2%. The recovery averaged 90.4 +/- 8.9%. A plasma profile following i.v. administration of naloxone in one normal healthy volunteer is presented.
Asunto(s)
Naloxona/sangre , Antagonistas de Narcóticos/sangre , Análisis de Varianza , Cromatografía Líquida de Alta Presión/economía , Cromatografía Líquida de Alta Presión/métodos , Electroquímica , Humanos , Inyecciones Intravenosas , Masculino , Naloxona/administración & dosificación , Naloxona/química , Naloxona/farmacocinética , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/química , Antagonistas de Narcóticos/farmacocinética , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Agonistas de Receptores de Serotonina/análisis , Sumatriptán/análisis , Tomografía Computarizada de Emisión , Vasoconstrictores/análisisRESUMEN
Buspirone is a member of the azapirone group of anxiolytic drugs and has one major metabolite, 1-(2-pyrimidinyl)piperazine (1-PP). The analyte, its metabolite and the internal standard were extracted from plasma utilizing solid-phase extraction columns. Chromatography was performed using isocratic reversed-phase high-performance liquid chromatography with coulometric end-point detection. The calibration graph was linear over the range 0-50 ng ml-1 of plasma. The lower limits of quantitation for buspirone and 1-PP were 0.5 and 2 ng ml-1, respectively, when 1 ml of plasma was extracted. The intra-assay relative standard deviations (RSD) over the range of the calibration graph varied from 4 to 12.5% for buspirone and 1-PP. The inter-assay RSD was 6.9% for 1-PP and 9.6% for buspirone. The recovery averaged 96% for buspirone and 66% for 1-PP. Plasma profiles of buspirone and 1-PP following oral dosing are presented.
Asunto(s)
Buspirona/análogos & derivados , Buspirona/sangre , Agonistas de Receptores de Serotonina/sangre , Adulto , Biotransformación , Buspirona/farmacocinética , Calibración , Cromatografía Líquida de Alta Presión , Electroquímica , Humanos , Indicadores y Reactivos , Masculino , Estándares de Referencia , Agonistas de Receptores de Serotonina/farmacocinéticaRESUMEN
Previous animal studies have shown the antinociceptive effects of intrathecal clonidine and intrathecal morphine to be synergistic. This study investigated the intrathecal administration of multiple doses of this drug combination to examine the rate of development of tolerance and to determine whether there was any toxic effect on the spinal cord. Rats with indwelling intrathecal catheters were given saline, morphine (2.5-7.5 micrograms), clonidine (17.5 micrograms), or clonidine (17.5 micrograms) plus morphine (1 microgram) intrathecally twice daily for 4 1/2 days (total of 9 doses). Hot plate and tail flick tests were conducted after the first, fifth and ninth doses. After the ninth dose animals were killed and their spinal cords were removed for histological examination. Tolerance developed to the antinociceptive effects of the drug combination, but at a slower rate than to morphine alone. No evidence of toxicity or injury to the spinal cord was observed other than changes which could be ascribed to the presence of the catheter.
Asunto(s)
Clonidina/farmacología , Tolerancia a Medicamentos , Morfina/farmacología , Animales , Quimioterapia Combinada , Inyecciones Espinales , Masculino , Dimensión del Dolor , Ratas , Médula Espinal/efectos de los fármacosRESUMEN
This study investigated behavioural effects of the toxic pethidine metabolite, norpethidine, in rats and its interactions with reserpine, apomorphine and physostigmine. Following intraperitoneal administration, brain concentrations of norpethidine reached a plateau after 20-40 min and remained elevated for 2 h. In the dose range 0.06-0.18 mmol/kg, norpethidine induced myoclonic jerks, a characteristic splayed posture, and episodes of exaggerated shivering. Forward locomotion, grooming, yawning and rearing were suppressed. Seizures and reverse locomotion occurred occasionally. Administration of reserpine 1 h prior to norpethidine, or of apomorphine or physostigmine 15 min after norpethidine, did not alter the norpethidine-induced behaviours; neither did norpethidine block the effects of apomorphine or physostigmine. The characteristic profile of behaviours induced by norpethidine make this toxicant readily amenable to animal studies. Our results indicate that its mechanism of action is unlikely to involve dopaminergic or cholinergic pathways.
Asunto(s)
Conducta Animal/efectos de los fármacos , Inhibidores de la Colinesterasa/toxicidad , Meperidina/análogos & derivados , Animales , Apomorfina/farmacología , Química Encefálica , Inhibidores de la Colinesterasa/análisis , Inhibidores de la Colinesterasa/sangre , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Meperidina/análisis , Meperidina/sangre , Meperidina/toxicidad , Fisostigmina/farmacología , Distribución Aleatoria , Ratas , Ratas Wistar , Reserpina/farmacologíaRESUMEN
Morphine was assayed using a simple two step solvent extraction--acid back extraction sample preparation method, coupled with normal phase high-performance liquid chromatography (HPLC) and dual electrode coulometric detection. HPLC is performed with a 1.0 M Tris-methanol (5:95) mobile phase with subtle pH adjustments to separate morphine and internal standard from any interfering compounds. The use of normal phase HPLC (silica column) substantially reduces problems from interfering lipophilic substances sometimes encountered with reverse phase HPLC following solvent extraction and which would otherwise require more time-consuming sample preparation. Dual electrode detection further improves the selectivity for morphine and gives excellent sensitivity (0.5 ng mL-1), reproducibility and stability for automated sample injection. This method has proven suitable for pharmacokinetic studies of morphine.