RESUMEN
Ophthalmologists and interventional radiologists are not the only professionals for whom diseases of the efferent tear duct system occupy centre stage; this applies also to ENT specialists involving endonasal conservative or surgical treatment. On the basis of current knowledge and taking account of results yielded by own research in recent years and of clinical aspects, we here give an overview of basic knowledge on the anatomy and physiology of the nasolacrimal system. In doing so functional aspects regarding tear transport as well as embryological and pathophysiological issues are integrated.
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Modelos Anatómicos , Modelos Biológicos , Conducto Nasolagrimal/anatomía & histología , Conducto Nasolagrimal/fisiología , Lágrimas/metabolismo , HumanosRESUMEN
BACKGROUND: Dry eye is one of the most common eye surface disorders. Patients suffer in particular from annoying subjective symptoms that compromise quality of life. The aim of the study was to find out when patients consult ophthalmologists in Germany and what symptoms they present. PATIENTS/MATERIAL AND METHODS: 170 patients treated at ophthalmological practices in Bavaria, Saxony and Saxony-Anhalt with dry eye were surveyed regarding their symptoms. RESULTS: The majority of those questioned were 40 years of age or older (88â%) (average: 60), female (59â%) and described a variety of subjective symptoms (65â%). More than five different concurrent symptoms were named. There is a recognisable increase in cases - by more than 3.5 times - at the age of forty (in women) and fifty (in men). CONCLUSIONS: We hope to contribute with the data obtained to a more complete understanding of this highly complex pathological process. A further aim is to facilitate recognition of this mostly chronic condition in its early stages when the symptoms are still poorly defined. The data on the German population obtained here should become part of a comparative analysis within the international context. Despite considerable scientific effort, dry eye remains a difficult challenge for both patients and attending physicians.
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Síndromes de Ojo Seco/epidemiología , Síndromes de Ojo Seco/psicología , Calidad de Vida/psicología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Femenino , Alemania/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Distribución por Sexo , Adulto JovenRESUMEN
Numerical simulations are a valuable tool in the field of tissue engineering for cartilage repair and can help to understand which mechanical properties affect the behavior of chondrocytes and contribute to the success or failure of surrogate materials as implants. However, special attention needs to be paid when identifying corresponding material parameters in order to provide reliable numerical predictions of the material's response. In this study, we identify hyperelastic material parameters for numerical simulations in COMSOL Multiphysics® v. 5.6 for human articular cartilage and two surrogate materials, commercially available ChondroFillerliquid, and oxidized alginate-gelatin (ADA-GEL) hydrogels. We consider several hyperelastic isotropic material models and provide separate parameter sets for the unconditioned and the conditioned material response, respectively, based on previously generated experimental data including both compression and tension experiments. We compare a direct parameter identification approach assuming homogeneous deformation throughout the specimen and an inverse approach, where the experiments are simulated using a finite element model with realistic boundary conditions in COMSOL Multiphysics® v. 5.6. We demonstrate that it is important to consider both compression and tension data simultaneously and to use the inverse approach to obtain reliable parameters. The one-term Ogden model best represents the unconditioned response of cartilage, while the conditioned response of cartilage and ADA-GEL is equally well represented by the two-term Ogden and five-term Mooney-Rivlin models. The five-term Mooney-Rivlin model is also most suitable to model the unconditioned response of ADA-GEL. For ChondroFillerliquid, we suggest using the five-term Mooney-Rivlin or two-term Ogden model for the unconditioned and the two-term Ogden model for the conditioned material response. These results will help to choose appropriate material models and parameters for simulations of whole joints or to advance mechanical-stimulation assisted cartilage tissue engineering in the future.
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Cartílago Articular , Cartílago Articular/fisiología , Condrocitos , Elasticidad , Análisis de Elementos Finitos , Gelatina , Humanos , Hidrogeles , Estrés Mecánico , Ingeniería de TejidosRESUMEN
The amphiphilic surfactant proteins B (SP-B) and C (SP-C) are tightly bound to phospholipids. These proteins play important roles in maintaining the surface tension-lowering properties of pulmonary surfactant. Surfactant protein A (SP-A) and D (SP-D) are hydrophilic and are thought to have a role in recycling surfactant and, especially, in improving host defense in the lung. Moreover, SP-A supports the hydrophobic surfactant proteins B and during surfactant subtype assembly and inhibits the secretion of lamellar bodies into the alveolar space. During recent years surfactant proteins have also been detected at locations outside the lung such as the lacrimal apparatus. In this review, the latest information regarding SP function and regulation in the human lacrimal system, the tear film and the ocular surface is summarised with regard to dry eye, rheological and antimicrobial properties of the tear film, tear outflow, certain disease states and possible therapeutic perspectives.
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Síndromes de Ojo Seco/fisiopatología , Aparato Lagrimal/fisiopatología , Pulmón/fisiopatología , Surfactantes Pulmonares/metabolismo , Lágrimas/fisiología , Humanos , ReologíaRESUMEN
The mechanical behavior of cartilage tissue plays a crucial role in physiological mechanotransduction processes of chondrocytes and pathological changes like osteoarthritis. Therefore, intensive research activities focus on the identification of implant substitute materials that mechanically mimic the cartilage extracellular matrix. This, however, requires a thorough understanding of the complex mechanical behavior of both native cartilage and potential substitute materials to treat cartilage lesions. Here, we perform complex multi-modal mechanical analyses of human articular cartilage and two surrogate materials, commercially available ChondroFillerliquid, and oxidized alginate-gelatin (ADA-GEL) hydrogels. We show that all materials exhibit nonlinearity and compression-tension asymmetry. However, while hyaline cartilage yields higher stresses in tension than in compression, ChondroFillerliquid and ADA-GEL exhibit the opposite trend. These characteristics can be attributed to the materials' underlying microstructure: Both cartilage and ChondroFillerliquid contain fibrillar components, but the latter constitutes a bi-phasic structure, where the 60% nonfibrillar hydrogel proportion dominates the mechanical response. Of all materials, ChondroFillerliquid shows the most pronounced viscous effects. The present study provides important insights into the microstructure-property relationship of cartilage substitute materials, with vital implications for mechanically-driven material design in cartilage engineering. In addition, we provide a data set to create mechanical simulation models in the future.
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Cartílago Articular , Condrocitos , Humanos , Cartílago Hialino , Hidrogeles , Mecanotransducción Celular , Ingeniería de TejidosRESUMEN
Woundhealing disorders characterized by impaired or delayed re-epithelialization are a serious medical problem that is painful and difficult to treat. Gelsolin (GSN), a known actin modulator, supports epithelial cell regeneration and apoptosis. The aim of this study was to estimate the potential of recombinant gelsolin (rhu-pGSN) for ocular surface regeneration to establish a novel therapy for delayed or complicated wound healing. We analyzed the influence of gelsolin on cell proliferation and wound healing in vitro, in vivo/ex vivo and by gene knockdown. Gelsolin is expressed in all tested tissues of the ocular system as shown by molecular analysis. The concentration of GSN is significantly increased in tear fluid samples of patients with dry eye disease. rhu-pGSN induces cell proliferation and faster wound healing in vitro as well as in vivo/ex vivo. TGF-ß dependent transcription of SMA is significantly decreased after GSN gene knockdown. Gelsolin is an inherent protein of the ocular system and is secreted into the tear fluid. Our results show a positive effect on corneal cell proliferation and wound healing. Furthermore, GSN regulates the synthesis of SMA in myofibroblasts, which establishes GSN as a key protein of TGF-ß dependent cell differentiation.
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Conjuntiva/metabolismo , Córnea/metabolismo , Síndromes de Ojo Seco/genética , Gelsolina/genética , Repitelización/genética , Actinas/genética , Actinas/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Conjuntiva/patología , Córnea/patología , Síndromes de Ojo Seco/sangre , Síndromes de Ojo Seco/patología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Párpados/citología , Párpados/metabolismo , Femenino , Gelsolina/sangre , Regulación de la Expresión Génica , Humanos , Aparato Lagrimal/metabolismo , Aparato Lagrimal/patología , Masculino , Ratones , Miofibroblastos/citología , Conducto Nasolagrimal/citología , Conducto Nasolagrimal/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Cicatrización de Heridas/genéticaRESUMEN
Pulmonary surfactant is broadly known to keep the lung dry, clean and open by lowering the surface tension of the fluid-film that lines the alveoli. The surfactant's protein component, the so called surfactant proteins (SPs), make up a multifunctional protein family. In addition to the four "classical" surfactant proteins (SP-A, SP-B, SP-C and SP-D), which possess immunologic as well as surfactant regulatory properties, two novel putative surfactant proteins (SFTA2 and SFTA3) have recently been described. Neither of them shows sequential nor structural similarity with the already known surfactant proteins. However, bioinformatic analyses as well as first molecular-biological studies reveal properties that have already been described for known surfactant proteins. In our present work we introduce a technique to synthesize, purify and stabilize recombinant SFTA3 derived from the human embryonic kidney cell line HEK 293T. This will provide investigators with a valuable source of further examination and characterization of this fascinating novel member of the surfactant protein family.
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Cistatina A/genética , Cistatina A/metabolismo , Células HEK293/fisiología , Ingeniería de Proteínas/métodos , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Clonación Molecular/métodos , Cistatina A/química , Humanos , Proteínas Recombinantes/químicaRESUMEN
INTRODUCTION: Pathological formation of blood vessels plays a key role in the growth and metastasis of tumors and also in several serious ophthalmological diseases such as wet age-related macular degeneration (AMD) or diabetic retinopathy. In AMD treatment, aflibercept (tradename EYLEA®) is used to deactivate the underlying pathological neovascularisation. Aflibercept is a recombinant fusion protein which binds to vascular endothelial growth factor (VEGF) receptors, thereby inhibiting VEGF pathway activation. VEGF is one of the most important angiogenesis factors. OBJECTIVE: This analysis investigates lasting efficacy of aflibercept in vitro for later application as therapeutic agent against macular degeneration (AMD). MATERIAL AND METHODS: VEGF-ELISA assays were performed to investigate binding affinities at different aflibercept concentrations. The impact of VEGF on the proliferation of human umbilical vein endothelial cells (HUVEC) was investigated using proliferation assays. Moreover, time-dependent kinetic studies were performed to analyze different aflibercept storage durations with regard to its inhibitory capabilities on human VEGF. RESULTS AND CONCLUSION: Our results reveal that aflibercept significantly lowers the amount of unbound VEGF as well as the proliferation rate of HUVEC. Moreover, in contrast to specifications given by the manufacturer, aflibercept retains its full inhibitory effect up to at least 120h after transference from the original vial into the injection syringe.
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Proliferación Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/administración & dosificación , Línea Celular , Proliferación Celular/fisiología , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Almacenaje de Medicamentos , HumanosRESUMEN
Surfactant proteins are broadly understood to be an important structural and functional part of the lung surfactant system. These proteins influence the intra-alveolar surface tension and contribute to innate immunity of the lung. Beside the four already known surfactant proteins SP-A, SP-B, SP-C and SP-D, two novel SPs (SP-G/SFTA2 and SP-H/SFTA3) have recently been described. These show no sequential or structural similarity with the already known SPs. However, bioinformatic prediction tools suggest physicochemical properties, which have already been described for other surfactant proteins. Although it is known that SFTA2 and SFTA3 are expressed in different human tissues, their distinct functional properties remain unclear. Here, we describe the establishment of a stable expression system for recombinant SFTA3 protein synthesis in Escherichia coli. This gives rise to future experiments with the overall aim to further examine and characterize this novel protein in more detail.
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Clonación Molecular/métodos , Escherichia coli/genética , Escherichia coli/metabolismo , Ingeniería de Proteínas/métodos , Proteínas Asociadas a Surfactante Pulmonar/química , Proteínas Asociadas a Surfactante Pulmonar/metabolismo , Secuencia de Aminoácidos , Humanos , Datos de Secuencia Molecular , Proteínas Asociadas a Surfactante Pulmonar/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
PURPOSE: Surfactant proteins (SPs) originally identified in lung tissue are important players in the innate immune system. Beyond this, they contribute to stability and rheology of gaseous or aqueous interphases. In the present study, we determined the expression and presence of SPs (A, B, C and D) in different areas of the human larynx. METHODS: mRNA expression of SP-A, -B, -C and -D was analyzed by means of RT-PCR in healthy samples of epiglottis, vocal and vestibular folds, subglottis and trachea. Distribution and localization of all four SPs were analyzed by Western blot and immunohistochemistry in healthy human tissue samples. RESULTS: All four SPs were detected at the mRNA- and protein level in the human larynx as well as by means of immunohistochemistry in the different tissue samples of the human larynx. CONCLUSION: The results reveal that all four SPs are produced with different expression patterns within the human larynx. Based on the known functions, our results suggest that SPs might be involved in maintaining mucus rheology and subsequently they could be essential components for proper phonation. Moreover, the proteins seem to play a role in immune defense of the larynx.
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Laringe/metabolismo , Proteínas Asociadas a Surfactante Pulmonar/metabolismo , Cadáver , Femenino , Humanos , Masculino , Especificidad de Órganos , Distribución TisularRESUMEN
The role of dopamine in d-amphetamine-induced euphoria has not been systematically examined in normal volunteers. Therefore, we examined the effects of the dopamine antagonist, pimozide, on responses to d-amphetamine in healthy volunteers, using a within-subjects, double-blind design. Ten subjects received single oral doses of d-amphetamine (0, 10, 20 mg) 2 hours following pretreatment with pimozide (0, 1, 2 mg). Subjective, behavioral, and physiological effects were assessed predrug and for 3 hours after d-amphetamine administration. d-Amphetamine alone produced prototypic effects on a variety of measures, including euphoria and drug liking. Pimozide did not produce any effects when administered alone and produced inconsistent effects on responses to d-amphetamine. Although higher doses of pimozide may be needed to antagonize the euphorigenic effects of d-amphetamine, these results raise the possibility that the role of dopamine in the subjective effects of stimulants may be more complex than initially appreciated.
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Estimulantes del Sistema Nervioso Central/farmacología , Dextroanfetamina/farmacología , Dopaminérgicos/farmacología , Antagonistas de Dopamina/farmacología , Euforia/efectos de los fármacos , Pimozida/farmacología , Adulto , Afecto/efectos de los fármacos , Nivel de Alerta/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Euforia/fisiología , Femenino , Humanos , Masculino , Premedicación , Desempeño Psicomotor/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacos , Valores de ReferenciaRESUMEN
Recent clinical reports indicate that combined administration of phentermine and fenfluramine may have useful effects in the treatment of drug abuse. The present study was designed to evaluate the subjective and mood-altering effects of these drugs, alone and in combination, in normal healthy volunteers. Seven male and five female volunteers participated in an eight-session, double-blind study in which each subject received each of the following drug conditions: d-amphetamine (10 and 20 mg), phentermine (30 mg), fenfluramine (40 and 80 mg), phentermine (30 mg) with fenfluramine (40 mg), phentermine (30 mg) with fenfluramine (80 mg), and placebo. Sessions were conducted in a laboratory setting two or three days a week. Subjects completed standardized self-report questionnaires and psychomotor tests before and at regular intervals after each drug administration. Phentermine produced effects that were similar to those of d-amphetamine, whereas fenfluramine produced different and apparently aversive effects (e.g., it increased measures of anxiety and confusion). Phentermine reduced the apparently aversive effects of fenfluramine when the two drugs were given together. These results suggest that the combination of phentermine and fenfluramine would have a low potential for abuse.
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Quimioterapia Combinada , Fenfluramina/farmacología , Fentermina/farmacología , Adulto , Femenino , Humanos , Masculino , Valores de ReferenciaRESUMEN
It was previously postulated on the basis of clinical data that the cardiovascular sequelae of extracorporeal whole-body hyperthermia (e-WBH), i.e., hypotension (which requires catecholamine support) results in unique nephrotoxicity in combination with select chemotherapeutic agents. In an attempt to explain this phenomenon, we mimicked e-WBH physiological conditions in a rat model. Animals were treated with and without ifosfamide (IFO) and/or carboplatin (CBDCA) at 37 degrees C or 41.5-41.8 degrees C, with blood pressure monitoring and catecholamine support comparable to the clinical setting. Ex vivo post-treatment data (24 h) from artificially perfused kidneys (i.e., histology, urine volume, perfusion rate, glomerular filtration rate, and the reabsorption of sodium, glucose, and water) demonstrated unique toxicity including proximal tubular necrosis for the combination of WBH and IFO, for WBH and CBDCA and for WBH and IFO plus CBDCA, but not for IFO and CBDCA without WBH. These data, considered together with results derived from a subsequent clinical trial and the laboratory work of others were consistent with the hypothesis.
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Antineoplásicos Alquilantes/toxicidad , Antineoplásicos/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Carboplatino/toxicidad , Hipertermia Inducida/efectos adversos , Hipotensión/etiología , Ifosfamida/toxicidad , Enfermedades Renales/etiología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carboplatino/administración & dosificación , Carboplatino/farmacología , Terapia Combinada , Hipertermia Inducida/métodos , Hipotensión/inducido químicamente , Ifosfamida/administración & dosificación , Ifosfamida/farmacología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Studies with laboratory animals have consistently demonstrated a role for dopamine in mediating the discriminative stimulus (i.e., interoceptive) effects of amphetamine. For example, D2 dopamine agonists mimic the discriminative stimulus effects of amphetamine and D1 and D2 dopamine antagonists generally block them. The discriminative stimulus effects of drugs in animals are believed to parallel their subjective effects in humans. Therefore, it is often assumed that dopamine plays a role in amphetamine-induced subjective effects in humans and it would be reasonable to expect that dopamine antagonists would block the subjective effects of amphetamine. Few studies have tested this hypothesis directly, and those that have have yielded inconsistent results. This paper will review data regarding the effects of dopamine agonists and antagonists on the discriminative stimulus effects of amphetamine in animals and its subjective effects in humans. Possible explanations for the discrepancies between animal and human data will be discussed, and classical assumptions underlying the use of animal models of drug effects will be examined.
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Anfetamina/farmacología , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Animales , Interacciones Farmacológicas , HumanosRESUMEN
RATIONALE: Studies with laboratory animals and humans suggest that dopamine may play a role in maintaining cigarette smoking behavior via its interactions with nicotine. OBJECTIVES: This study was designed to replicate and extend previous findings showing that the dopamine D2 antagonist, haloperidol, produces blockade of smoking reward and compensatory increases in smoking. METHODS: We studied 20 subjects in a 2x3 within-subjects design, with nicotine-containing or denicotinized cigarettes crossed with oral placebo, haloperidol 1 mg, or haloperidol 2 mg. Subjects attended six sessions during which they received one of the cigarette/drug combinations, and smoked under both controlled and ad libitum conditions. Cigarette and mood ratings and smoking behavior were assessed. RESULTS: Haloperidol reduced the number of cigarettes smoked and the carbon monoxide boost associated with both types of cigarettes, at doses that did not appear to produce clinically significant behavioral effects. CONCLUSIONS: Dopamine appears to play a role in mediating smoking behavior, but this may occur through a non-nicotine mechanism.
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Antagonistas de Dopamina/uso terapéutico , Haloperidol/uso terapéutico , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Fumar/tratamiento farmacológico , Adolescente , Adulto , Análisis de Varianza , Método Doble Ciego , Femenino , Humanos , Masculino , Fumar/psicologíaRESUMEN
A double-blind, placebo-controlled cross-over study was conducted to determine the effects of carbamazepine on the acute physiological and subjective responses to a single dose of smoked cocaine-base. Male cocaine users (N = 6) were given 400 mg carbamazepine or placebo, each for a period of 5 days. At the end of the 5-day period, a 40 mg dose of smoked cocaine was administered. The results showed a significantly higher heart rate, diastolic blood pressure elevation, and blood pressure-heart rate product under the carbamazepine compared to the placebo condition. There were no effects of carbamazepine on the subjective responses from cocaine. The increase in cardiovascular functions indicates a need to be cautious in the use of carbamazepine in the treatment of cocaine abusers.
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Carbamazepina/farmacología , Cocaína/farmacología , Administración por Inhalación , Adulto , Presión Sanguínea/efectos de los fármacos , Cocaína/administración & dosificación , Método Doble Ciego , Electrocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
RATIONALE: The role of endogenous opiate systems in cigarette smoking remains unclear. In laboratory animals, opiate antagonists block many of the effects of nicotine, but in humans they do not consistently alter smoking behavior. OBJECTIVE: This study explored the effects of naltrexone, alone and in combination with nicotine, on smoking behavior. METHODS: In a double-blind, double-dummy, within-subjects design, 19 regular smokers received four treatments of 1 week duration: naltrexone tablet (50 mg) plus placebo skin patch, placebo tablet plus nicotine skin patch (21 mg/24 h), naltrexone tablet plus nicotine skin patch, and placebo tablet plus placebo skin patch. During each treatment, subjects rated their responses to nicotine-containing and denicotinized cigarettes in the laboratory, and to their own brand of cigarette smoked ad libitum outside the laboratory. RESULTS: Pretreatment with the nicotine patch attenuated smoking-induced decreases in craving, negative affect, and rates of ad lib smoking, and potentiated the aversiveness of a cigarette. Naltrexone reversed these effects of the nicotine patch, and produced negative effects on mood. CONCLUSIONS: The blockade of nicotine's effects by naltrexone supports a role for opioid mechanisms in cigarette smoking.
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Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Nicotina/antagonistas & inhibidores , Fumar/fisiopatología , Fumar/psicología , Adulto , Afecto/efectos de los fármacos , Análisis de Varianza , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos , Fumar/sangre , Síndrome de Abstinencia a Sustancias/etiología , Síndrome de Abstinencia a Sustancias/prevención & control , Encuestas y CuestionariosRESUMEN
The purpose of this study was to compare the subjective effects of the selective serotonin reuptake inhibitor, paroxetine, to those of the prototypic stimulant, d-amphetamine. Ten healthy volunteers attended 5 sessions and received paroxetine (10, 20, 50 mg), d-amphetamine (20 mg), and placebo. Subjective effects were measured at regular intervals for 26-30 h. Paroxetine and d-amphetamine produced highly dissimilar effects on mood. For example, whereas d-amphetamine increased ratings of euphoria, drug high, and desire for drug, paroxetine produced no effects on these measures. Conversely, whereas paroxetine increased ratings of Confusion and Fatigue, d-amphetamine did not. These findings suggest that serotonin does not play a significant role in mediating the positive subjective effects of stimulant drugs.
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Afecto/efectos de los fármacos , Paroxetina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adulto , Dextroanfetamina/farmacología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Euforia/efectos de los fármacos , Femenino , Humanos , Masculino , Motivación , Inventario de PersonalidadRESUMEN
Despite its ubiquitous consumption in the natural environment, caffeine has not been a reliable reinforcer in laboratory settings. The reinforcing effects of caffeine are greater in caffeine-dependent subjects relative to non-dependent subjects, but the mechanism underlying this difference remains unclear. We hypothesized that deprivation from caffeine would produce alterations in subjective ratings of stimuli commonly associated with caffeine consumption. Specifically, we hypothesized that hedonic ratings of the coffee taste would be selectively enhanced following caffeine deprivation. Twelve regular caffeine users received acute doses of caffeine (300mg) or placebo after 33h of caffeine deprivation or non-deprivation. They rated the taste of coffee and sucrose, saccharin, and quinine solutions on intensity, bitterness, sweetness, pleasantness, and unpleasantness. Contrary to our hypothesis, subjects' ratings of the pleasantness of the coffee taste were not significantly altered by caffeine deprivation. However, subjects' ratings of the bitterness and sweetness of the coffee taste and ratings of the sucrose solution were altered by caffeine. Implications of these data for caffeine self-administration are discussed.
RESUMEN
Studies with laboratory animals have shown that dopamine antagonists block the rewarding and interoceptive effects of amphetamine. However, studies using dopamine antagonists with humans have not consistently shown blockade of amphetamine-induced euphoria. The unexpected results in humans may relate to the low doses of dopamine antagonists tested. The purpose of this study was to evaluate the effects of a relatively high acute dose (8 mg) of the dopamine receptor antagonist, pimozide, on responses to d-amphetamine (10 and 20 mg) in normal volunteers. Male and female volunteers (N = 12) attended six sessions on which they received pimozide or placebo (7:30 am) followed by d-amphetamine or placebo (9:30 am). Subjective, physiological and behavioral measures were obtained at baseline (7:15 am) and hourly over a 5 h period. d-Amphetamine and pimozide, when administered alone, produced significant and opposite effects on ratings of Elation and Vigor, as well as on psychomotor performance and physiological measures. However, there were few significant interactions between pimozide and d-amphetamine. Thus, pimozide failed to consistently antagonize the effects of d-amphetamine, even at doses of pimozide that had behavioral and physiological effects when administered alone. Possible reasons for lack of robust dopamine antagonism of amphetamine-induced euphoria in humans are discussed.