RESUMEN
The ability of methylene blue (MB) to inhibit the nitric oxide-induced stimulation of N-methyl-D-aspartate receptors has been suggested as a possible mechanism of MB's clinical antidepressant action. This study evaluated the alternative/additional mechanisms of the antidepressant effect of MB on biochemical and behavior levels. Selective inhibition of monoamine oxidase type A (MAO-A) is widely accepted as a major mechanism of the clinical antidepressant effect. MB and the related redox dyes toluidine blue O (TBO), thionine (TN), brilliant cresyl blue (BCB), and toluylene blue (TB) were reversible competitive inhibitors of both MAO-A and MAO-B and were highly selective toward MAO-A. TBO was the most potent inhibitor, followed by TN, BCB, MB, and TB. The dyes studied increased rat pineal N-acetylserotonin (NAS) and melatonin content, in accordance with our previous observations of the stimulating effect of selective inhibition of MAO-A on pineal melatonin biosynthesis. The redox dyes exerted antidepressant-like activity in frogs; that is, they suppressed the righting reflex in melatonin-primed frogs. This study's results indicate that selective inhibition of MAO-A might mediate the clinical antidepressant effect of MB through NAS stimulation and melatonin biosynthesis.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Melatonina/metabolismo , Azul de Metileno/farmacología , Monoaminooxidasa/metabolismo , Glándula Pineal/efectos de los fármacos , Reflejo/efectos de los fármacos , Serotonina/análogos & derivados , Animales , Anuros , Oxidación-Reducción , Ratas , Serotonina/metabolismoRESUMEN
The present study evaluates the relationship between cognitive impairment and the Dexamethasone Suppression Test (DST) in elderly persons suffering from depression. Twenty-nine subjects meeting DSM-III criteria for major depressive disorder (MDD) were assessed using the Global Deterioration Scale (GDS) and the DST. Plasma cortisol levels before and after receiving 0.5 mg dexamethasone were compared, and correlations were determined between GDS and postdexamethasone plasma cortisol levels. The results show that there is a positive correlation between the GDS scores and post-DEX cortisol levels (r = 0.57, p less than 0.005). It is suggested that increased activity of the HPA axis, seen in depression, could contribute to the cognitive impairments observed in this disorder.
Asunto(s)
Trastornos del Conocimiento/diagnóstico , Demencia/diagnóstico , Trastorno Depresivo/diagnóstico , Dexametasona , Hidrocortisona/sangre , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/sangre , Demencia/sangre , Trastorno Depresivo/sangre , Humanos , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
An abnormally high serum cholesterol level has been suggested as a biological marker for major depression. However, in 192 depressed and normal subjects, age and sex influenced serum cholesterol level, but the diagnosis of major depression did not.
Asunto(s)
Colesterol/sangre , Trastorno Depresivo/diagnóstico , Adolescente , Adulto , Factores de Edad , Anciano , Trastorno Depresivo/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
The clinical efficacy and adverse reaction profile of bupropion, an atypical antidepressant, was compared with the tricyclic imipramine in 63 elderly depressives. Patients were randomly assigned to treatment with 150 or 450 mg/day of bupropion, 150 mg/day of imipramine, or placebo for 35 days. Both doses of bupropion were equivalent to imipramine in antidepressant efficacy. The higher dose of bupropion had a more rapid onset of effect than the low dose and significantly greater anxiolytic activity than either imipramine or the lower dose. Both doses of bupropion had adverse reaction profiles strikingly similar to placebo and, in marked contrast to imipramine, did not produce sedation or anticholinergic side effects. Cognition improved equally in all groups. It was concluded that bupropion has therapeutic advantages over the tricyclics in the treatment of elderly depressives.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Imipramina/uso terapéutico , Propiofenonas/uso terapéutico , Factores de Edad , Anciano , Bupropión , Ensayos Clínicos como Asunto , Trastorno Depresivo/psicología , Método Doble Ciego , Femenino , Humanos , Masculino , Memoria/efectos de los fármacos , Persona de Mediana Edad , Placebos , Desempeño Psicomotor/efectos de los fármacos , Distribución AleatoriaRESUMEN
Dexamethasone (DEX, 0.5 mg orally at 11 PM) challenge was used for the assessment of hypothalamic-pituitary-adrenal (HPA) activity in 20 normal volunteers. Age and pre-DEX serum cortisol levels were theè evaluated as predictors of postDEX serum cortisol levels using step-wise multiple regression analysis. Both age and preDEX serum cortisol levels were significant predictors of postDEX serum cortisol levels. It is suggested that the adjustment for age and preDEX serum cortisol level could be useful for the interpretation of abnormal postDEX levels.
Asunto(s)
Dexametasona/farmacología , Hidrocortisona/sangre , Adolescente , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The effect of serotonin (5-HT) deficiency on hypothalamic-pituitary-adrenal (HPA) activity was investigated by using 5,7-dihydroxytryptamine (5,7-DHT) for the selective destruction of central 5-HT neurons, and corticosterone response to suppression by dexamethasone as the index of HPA activity. Dexamethasone was shown to significantly suppress serum corticosterone levels in sham-treated rats, but did not suppress corticosterone in the 5,7-DHT-lesioned animals. This finding supports the conclusion that 5-HT is involved in the negative feedback mechanism of HPA regulation.
Asunto(s)
5,7-Dihidroxitriptamina/farmacología , Encéfalo/metabolismo , Corticosterona/sangre , Dexametasona/farmacología , Dihidroxitriptaminas/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Serotonina/metabolismo , Animales , Encéfalo/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Sistema Hipófiso-Suprarrenal/fisiología , Ratas , Ratas EndogámicasRESUMEN
The level of inhibition of rat whole brain monoamine oxidase activity produced by the irreversible monoamine oxidase inhibitor phenelzine has been studied with or without concurrent cold restraint stress. We have found that phenelzine caused significantly less enzyme inhibition when given during a period of stress than during a control period. Thus, stress can reduce the in vivo potency of MAO inhibitors. This would be compatible with an increased production of the reversible, endogenous monoamine oxidase inhibitor, tribulin, competing for the active site of the enzyme.
Asunto(s)
Encéfalo/enzimología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Fenelzina/farmacología , Estrés Fisiológico/enzimología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Frío , Masculino , Ratas , Ratas Endogámicas , Restricción FísicaRESUMEN
1. This paper describes the effect of the serotonin precursor 5-hydroxytryptophan (5-HTP) on pineal melatonin synthesis young and old rats. 2. 5-HTP itself increased pineal melatonin levels in old rats but did not change melatonin concentrations in young rats kept under 12 hr/12 hr light/dark conditions. 3. After continuous exposure to light for 72 hrs, 5-HTP induced a significant increase in melatonin levels in young rats but did not change the 5-HTP effect on melatonin in old animals. 4. These results are discussed in consideration of previous reports of altered beta-receptor up-regulation by light in old animals, and suggest that the age-related decrease in melatonin synthesis is not entirely related to changes of the enzymatic machine for melatonin synthesis.
Asunto(s)
5-Hidroxitriptófano/farmacología , Envejecimiento/metabolismo , Luz , Melatonina/biosíntesis , Animales , Masculino , Glándula Pineal/efectos de los fármacos , Glándula Pineal/metabolismo , Ratas , Ratas EndogámicasRESUMEN
1. Clorgyline increased pineal melatonin and N-acetylserotonin (NAS) and decreased 5-hydroxyindoleacetic acid (5-HIAA) content in 3 and 12 months of age male Sprague-Dawley rats kept under 12:12 h light: dark schedule. Exposure to light for 24 h before clorgyline administration resulted in additional elevation of NAS and melatonin. NAS and melatonin levels after clorgyline injections were significantly higher while 5-HIAA levels were significantly lower in young than in middle-aged rats. 2. The 5-HIAA/5-HT ratio (index of monoamine oxidase activity) was higher in middle-aged than in young rats suggesting the lesser degree of clorgyline-induced inhibition of MAO-A in old than in young rats. 3. It is suggested that melatonin response to a single dose of the selective MAO-A inhibitor might be used for the assessment of the aging changes of the rat (and human) pineals.
Asunto(s)
Envejecimiento/metabolismo , Clorgilina/farmacología , Melatonina/biosíntesis , Glándula Pineal/metabolismo , Animales , Ácido Hidroxiindolacético/metabolismo , Luz , Masculino , Glándula Pineal/efectos de los fármacos , Ratas , Ratas Endogámicas , Serotonina/análogos & derivados , Serotonina/metabolismoRESUMEN
We have reported that clorgyline-induced stimulation of pineal melatonin biosynthesis could be augmented by the exposure to 24h of constant light in young but not in aged rats. Aging is associated with the declined integrity of the suprachiasmatic nuclei (SCN), the major station of the light signal passage from the retina to the pineal gland. The present study aimed to investigate whether SCN integrity is essential for clorgyline effects on pineal melatonin biosynthesis in light-primed rats. Clorgyline (2.5 mg/kg, s.c.) was administered to sham-operated and SCN-lesioned Sprague-Dawley rats kept under regular light/dark cycle or exposed to 24h of constant light. Pineal melatonin and related indoles were evaluated by HPLC-fluorimetric procedure. Clorgyline stimulated pineal melatonin biosynthesis in both SCN-lesioned and sham-operated rats kept under regular light/dark cycle. Exposure to constant light (for 24h) augmented clorgyline-induced stimulation of melatonin biosynthesis in sham-operated rats, but not in SCN-lesioned animals. The obtained results suggest that decline in SCN activity (e.g., age-associated) might contribute to previously reported attenuation of clorgyline-induced stimulation of melatonin biosynthesis in light-primed aged rats.
Asunto(s)
Clorgilina/farmacología , Melatonina/biosíntesis , Glándula Pineal/metabolismo , Núcleo Supraquiasmático/fisiología , Animales , Oscuridad , Ácido Hidroxiindolacético/metabolismo , Luz , Masculino , Glándula Pineal/efectos de los fármacos , Glándula Pineal/efectos de la radiación , Ratas , Ratas Sprague-Dawley , Serotonina/análogos & derivados , Serotonina/metabolismoRESUMEN
Selective monoamine oxidase (MAO) A inhibitors and cold-immobilization stress (which increases the production of the endogenous MAO-A inhibitor, tribulin) stimulate rat pineal melatonin biosynthesis in Sprague-Dawley and Fisher 344N rats. Considering the hyperactive sympathetic response of the hypertensive rats, it was interesting to compare the effect of clorgyline and cold-immobilization stress on pineal melatonin and related indoles levels in SHR and WKY rats (HPLC-fluorimetric method). Clorgyline (0.5 mg/kg and 1.5 mg/kg, sc) induced a higher elevation of pineal melatonin and N-acetylserotonin (NAS) in SHR than in WKY rats. Cold immobilization stress resulted in lower serotonin, and higher NAS levels in SHR than in WKY rats with similar elevations in melatonin levels. Our results suggest increased serotonin conversion into NAS and decreased NAS conversion into melatonin with decreased production of tribulin in SHR in comparison with WKY rats.
Asunto(s)
Clorgilina/farmacología , Isatina , Isoenzimas/antagonistas & inhibidores , Melatonina/metabolismo , Inhibidores de la Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Glándula Pineal/metabolismo , Serotonina/análogos & derivados , Animales , Frío , Ácido Hidroxiindolacético/metabolismo , Masculino , Glándula Pineal/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Restricción Física , Serotonina/metabolismo , Especificidad de la EspecieRESUMEN
Pineal melatonin and related indoles levels were higher in Roman high- than in Roman low-avoidance rats, while 5-HIAA/5-HT ratio, as an index of MAO activity was higher in low- than in high-avoidance rats. Clorgyline stimulated pineal melatonin biosynthesis in both lines of rats. However, melatonin and N-acetylserotonin levels remained higher and 5-HIAA levels remained lower in the high avoidance rats treated with low dose (0.5 mg/kg) while treatment with 1.0 mg/kg of clorgyline eliminated the differences in melatonin production between high- and low-avoidance rats.
Asunto(s)
Reacción de Prevención/fisiología , Clorgilina/farmacología , Melatonina/biosíntesis , Glándula Pineal/metabolismo , Ratas Endogámicas/metabolismo , Ratas Endogámicas/psicología , Animales , Ácido Hidroxiindolacético/metabolismo , Masculino , Ratas , Serotonina/análogos & derivados , Serotonina/metabolismoRESUMEN
It has been reported that selective MAO-A inhibitors, clorgyline and brofaromine, but not the MAO-B inhibitors, deprenyl and pargyline, stimulated rat pineal melatonin synthesis in humans and animals. Recent studies, however, found no effect of moclobemide, a selective MAO-A inhibitor, on human plasma melatonin levels. Present study found that in vitro moclobemide produced very weak stimulation of rat pineal NAT activity. However, in vivo moclobemide induced a significant increase of rat pineal NAS and melatonin content, and a dramatic decrease of 5-HIAA content (HPLC-fluorimetric procedure). Moclobemide's effect on melatonin and related indoles could be detected as early as 30 min after the injection and lasted, at least, for 2 h. The possible reasons for discrepancies between human and animal data are discussed.
Asunto(s)
Benzamidas/farmacología , Melatonina/biosíntesis , Inhibidores de la Monoaminooxidasa/farmacología , Acetiltransferasas/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Técnicas In Vitro , Cinética , Masculino , Moclobemida , Monoaminooxidasa/metabolismo , Glándula Pineal/efectos de los fármacos , Glándula Pineal/enzimología , Glándula Pineal/metabolismo , Ratas , Ratas Endogámicas F344 , Espectrometría de FluorescenciaRESUMEN
Acute administration of the irreversible MAO-A inhibitor, clorgyline (2.0 mg/kg, s.c.) and the reversible MAO-A inhibitor, moclobemide (10 mg/kg, s.c.), increased rat pineal melatonin and related indoles content (HPLC-fluorimetric method). Chronic (21 days) administration of clorgyline attenuated the acute effect of clorgyline on pineal melatonin biosynthesis. The acute effect of moclobemide on melatonin biosynthesis was not affected by chronic moclobemide administration. The observed difference in the chronic effects of irreversible and reversible selective MAO-A inhibitors on melatonin biosynthesis could have clinical implications.
Asunto(s)
Melatonina/biosíntesis , Inhibidores de la Monoaminooxidasa/administración & dosificación , Monoaminooxidasa/metabolismo , Glándula Pineal/metabolismo , Animales , Benzamidas/administración & dosificación , Benzamidas/farmacología , Clorgilina/administración & dosificación , Clorgilina/farmacología , Femenino , Ácido Hidroxiindolacético/metabolismo , Moclobemida , Inhibidores de la Monoaminooxidasa/farmacología , Ratas , Ratas Endogámicas F344 , Serotonina/análogos & derivados , Serotonina/metabolismo , Factores de TiempoRESUMEN
Total suppression of righting reflex in frogs (Rana pipiens, 25-35 mg b.w.) was observed after combined administration of melatonin (12.5 mg/kg) and selective inhibitors of MAO-A: clorgyline (2.5 mg/kg) and moclobemide (50 mg/kg) but not MAO-B: selegiline (25 mg/kg) and Ro-19-6327 (50 mg/kg). None of these drugs alone affected the righting reflex. Clorgyline and selegiline selectively inhibited brain MAO-A and MAO-B activity (by more than 90%), resp. Frogs might represent a convenient model to study the selective MAO-A and B type inhibitors since they provide the opportunity to correlate behaviour and biochemical changes induced by MAO inhibitors.
Asunto(s)
Hipnóticos y Sedantes/farmacología , Melatonina/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Animales , Encéfalo/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Masculino , Postura , Rana pipiens , Reflejo/efectos de los fármacosRESUMEN
The response to administration of the specific monoamine oxidase A (MAO-A) blocker clorgyline was investigated in adult male Sprague-Dawley rats which were adrenalectomized four days prior to treatment or were additionally sympathectomized as newborns by injection of 6-hydroxydopamine. In both groups, the contents of pineal indoles melatonin and N-acetylserotonin were augmented, and the contents of 5-hydroxyindoleacetic acid and 5-hydroxyindoletryptophol decreased 90 min following clorgyline injections when compared to rats receiving saline. The observed responses were less pronounced in rats both adrenalectomized and sympathectomized. The results are in line with the hypothesis that preservation from oxidation of both MAO-A substrates, noradrenaline and serotonin, upon clorgyline administration contributes to the observed increase in melatonin biosynthesis thought to be associated with the anti-depressant effects of MAO inhibition.
Asunto(s)
Clorgilina/farmacología , Melatonina/biosíntesis , Oxidopamina/farmacología , Glándula Pineal/metabolismo , Adrenalectomía , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Serotonina/análogos & derivados , Serotonina/metabolismo , Simpatectomía QuímicaRESUMEN
Six months of administration of the selective MAO-B inhibitor, selegiline (l-deprenyl 0.25 mg/kg, s.c.) to aged female Fisher 344N rats suppressed MAO-A as well as MAO-B activity and increased serotonin (substrate for melatonin biosynthesis) and N-acetylserotonin (immediate melatonin precursor) levels in pineal glands taken from the animals during the night. Daytime values were unchanged by the treatment. The data suggest that stimulation of pineal melatonin biosynthesis might be one of the consequences of MAO-A inhibition contributing to life span prolongation induced by chronic selegiline treatment.
Asunto(s)
Envejecimiento/metabolismo , Indoles/metabolismo , Melatonina/metabolismo , Monoaminooxidasa/metabolismo , Glándula Pineal/metabolismo , Selegilina/farmacología , Animales , Femenino , Ratas , Ratas Endogámicas F344 , Valores de Referencia , Factores de TiempoRESUMEN
The chronopharmacological hypothesis of the mechanism of the antidepressant effect of MAO-A inhibitors predicts that clinical efficacy depends upon the time of the day at which the drugs are administered. In the present study moclobemide (10 mg/kg, s.c.) injected at the end of the light phase advanced the onset of the nighttime increase of the rat pineal melatonin biosynthesis while the same dose of drug injected at the end of the dark phase delayed the daytime decrease of melatonin biosynthesis. The results obtained suggest that the timing of MAO-A inhibitor administration should be considered in clinical practice.
Asunto(s)
Benzamidas/administración & dosificación , Melatonina/biosíntesis , Inhibidores de la Monoaminooxidasa/administración & dosificación , Glándula Pineal/metabolismo , Animales , Benzamidas/farmacología , Ritmo Circadiano , Femenino , Moclobemida , Inhibidores de la Monoaminooxidasa/farmacología , Ratas , Ratas Endogámicas F344 , Serotonina/análogos & derivados , Serotonina/metabolismo , Factores de TiempoRESUMEN
The bioprecursor amino acid MDL 72394 is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392, an irreversible selective MAO-A inhibitor. Pretreatment with the AADC inhibitor carbidopa, which does not penetrate the brain-blood barrier, prevents the liberation of the MAO-A inhibitor outside the brain and results in exclusive inhibition of brain MAO-A. We found that systemic administration of MDL 72394 (0.5 mg/kg, i.p.) stimulated rat pineal melatonin biosynthesis. Carbidopa, in a dose-dependent manner, attenuated or completely prevented MDL-induced stimulation of melatonin biosynthesis in the pineal gland located outside the blood-brain-barrier.
Asunto(s)
Encéfalo/metabolismo , Melatonina/biosíntesis , Inhibidores de la Monoaminooxidasa/farmacología , Glándula Pineal/metabolismo , Profármacos/farmacología , Tiramina/análogos & derivados , Animales , Carbidopa/administración & dosificación , Carbidopa/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Monoaminooxidasa/metabolismo , Ratas , Ratas Endogámicas F344 , Factores de Tiempo , Tiramina/farmacologíaRESUMEN
Cold-restrained stress increased rat pineal melatonin and N-acetylserotonin content. This effect was partially prevented by lorazepam. Serotonergic turnover (ratio of 5-hydroxyindole acetic acid to serotonin) was significantly decreased in stressed but not in stressed rats pretreated with lorazepam, suggesting stress-induced inhibition of monoamine oxidase (MAO). Literature data indicate that the same type of stress increases the production of the endogenous MAO inhibitor. The implication of stress-induced MAO inhibition on melatonin synthesis in anxiety and drug withdrawal is discussed.