RESUMEN
The role of the monoamines dopamine (DA) and serotonin (5HT) and the monoamine-metabolizing enzyme monoamine oxidase A (MAOA) have been repeatedly implicated in studies of alcohol use and dependence. Genetic investigations of MAOA have yielded conflicting associations between a common polymorphism (MAOA-LPR) and risk for alcohol abuse. The present study provides direct comparison of tissue-specific MAOA expression and the level of alcohol consumption. We analyzed rhesus macaque MAOA (rhMAOA) expression in blood from males before and after 12 months of alcohol self-administration. In addition, nucleus accumbens core (NAc core) and cerebrospinal fluid (CSF) were collected from alcohol access and control (no alcohol access) subjects at the 12-month time point for comparison. The rhMAOA expression level in the blood of alcohol-naive subjects was negatively correlated with subsequent alcohol consumption level. The mRNA expression was independent of rhMAOA-LPR genotype and global promoter methylation. After 12 months of alcohol use, blood rhMAOA expression had decreased in an alcohol dose-dependent manner. Also after 12 months, rhMAOA expression in the NAc core was significantly lower in the heavy drinkers, as compared with control subjects. The CSF measured higher levels of DA and lower DOPAC/DA ratios among the heavy drinkers at the same time point. These results provide novel evidence that blood MAOA expression predicts alcohol consumption and that heavy alcohol use is linked to low MAOA expression in both the blood and NAc core. Together, the findings suggest a mechanistic link between dampened MAOA expression, elevated DA and alcohol abuse.
Asunto(s)
Alcoholismo/enzimología , Monoaminooxidasa/biosíntesis , Consumo de Bebidas Alcohólicas/sangre , Consumo de Bebidas Alcohólicas/líquido cefalorraquídeo , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/metabolismo , Alcoholismo/sangre , Alcoholismo/líquido cefalorraquídeo , Alcoholismo/genética , Alelos , Animales , Estudios de Casos y Controles , Dopamina/líquido cefalorraquídeo , Dopamina/metabolismo , Expresión Génica , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Macaca mulatta , Masculino , Monoaminooxidasa/sangre , Monoaminooxidasa/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Serotonina/líquido cefalorraquídeo , Serotonina/metabolismoRESUMEN
CONTEXT: Recurrence of hyperprolactinemia after cabergoline withdrawal ranges widely from 36 to 80%. The Pituitary Society recommends withdrawal of cabergoline in selected patients. OBJECTIVE: Our aim was to evaluate recurrence of hyperprolactinemia in patients meeting The Pituitary Society guidelines. DESIGN: Patients were followed from the date of discontinuation to either relapse of hyperprolactinemia or the day of last prolactin test. SETTING: We conducted the study at an academic medical center. PATIENTS: Forty-six patients meeting Pituitary Society criteria (normoprolactinemic and with tumor volume reduction after 2 or more years of treatment) participated in the study. INTERVENTIONS: After withdrawal, if prolactin returned above reference range, another measurement was obtained within 1 month, symptoms were assessed by questionnaire, and magnetic resonance imaging was performed. MAIN OUTCOME MEASURES: We measured risk of and time to recurrence estimates as well as clinical predictors of recurrence. RESULTS: Mean age of patients was 50 +/- 13 yr, and 70% were women. Thirty-one patients had microprolactinomas, 11 had macroprolactinomas, and four had nontumoral hyperprolactinemia. The overall recurrence was 54%, and the estimated risk of recurrence by 18 months was 63%. The median time to recurrence was 3 months (range, 1-18 months), with 91% of recurrences occurring within 1 yr after discontinuation. Size of tumor remnant prior to withdrawal predicted recurrence [18% increase in risk for each millimeter (95% confidence interval, 3-35; P = 0.017)]. None of the tumors enlarged in the patients experiencing recurrence, and 28% had symptoms of hypogonadism. CONCLUSIONS: Cabergoline withdrawal is practical and safe in a subset of patients as defined by The Pituitary Society guidelines; however, the average risk of long-term recurrence in our study was over 60%. Close follow-up remains important, especially within the first year.
Asunto(s)
Ergolinas/uso terapéutico , Hiperprolactinemia/tratamiento farmacológico , Privación de Tratamiento , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Cabergolina , Ergolinas/efectos adversos , Femenino , Humanos , Hiperprolactinemia/diagnóstico , Hiperprolactinemia/epidemiología , Hiperprolactinemia/etiología , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/patología , Embarazo , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Pronóstico , Prolactinoma/complicaciones , Prolactinoma/tratamiento farmacológico , Prolactinoma/patología , Recurrencia , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
Schizophrenia is a widespread psychiatric disorder, affecting 1% of people. Despite this high prevalence, schizophrenia is not well treated because of its enigmatic developmental origin. We explore here the developmental etiology of endophenotypes associated with schizophrenia using a regulated transgenic approach in mice. Recently, a polymorphism that increases mRNA levels of the G-protein subunit Galphas was genetically linked to schizophrenia. Here we show that regulated overexpression of Galphas mRNA in forebrain neurons of mice is sufficient to cause a number of schizophrenia-related phenotypes, as measured in adult mice, including sensorimotor gating deficits (prepulse inhibition of acoustic startle, PPI) that are reversed by haloperidol or the phosphodiesterase inhibitor rolipram, psychomotor agitation (hyperlocomotion), hippocampus-dependent learning and memory retrieval impairments (hidden water maze, contextual fear conditioning), and enlarged ventricles. Interestingly, overexpression of Galphas during development plays a significant role in some (PPI, spatial learning and memory and neuroanatomical deficits) but not all of these adulthood phenotypes. Pharmacological and biochemical studies suggest the Galphas-induced behavioral deficits correlate with compensatory decreases in hippocampal and cortical cyclic AMP (cAMP) levels. These decreases in cAMP may lead to reduced activation of the guanine exchange factor Epac (also known as RapGEF 3/4) as stimulation of Epac with the select agonist 8-pCPT-2'-O-Me-cAMP increases PPI and improves memory in C57BL/6J mice. Thus, we suggest that the developmental impact of a given biochemical insult, such as increased Galphas expression, is phenotype specific and that Epac may prove to be a novel therapeutic target for the treatment of both developmentally regulated and non-developmentally regulated symptoms associated with schizophrenia.
Asunto(s)
Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Regulación del Desarrollo de la Expresión Génica/genética , Acetilcisteína/agonistas , Acetilcisteína/análogos & derivados , Acetilcisteína/antagonistas & inhibidores , Estimulación Acústica , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Antipsicóticos/uso terapéutico , Conducta Animal , Encéfalo/metabolismo , Encéfalo/patología , Trastornos del Conocimiento/tratamiento farmacológico , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , AMP Cíclico/análogos & derivados , AMP Cíclico/metabolismo , AMP Cíclico/farmacología , Modelos Animales de Enfermedad , Eritromicina/agonistas , Eritromicina/análogos & derivados , Eritromicina/antagonistas & inhibidores , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Miedo/efectos de los fármacos , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Haloperidol/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de Fosfodiesterasa/farmacología , Psicofísica , Reflejo de Sobresalto/genética , Rolipram/farmacología , Factores de TiempoRESUMEN
The glucocorticoid component of the stress response has been the subject of intense scientific scrutiny because of the wide ranging pathological consequences resulting from excess glucocorticoid exposure, including mood and anxiety disorders, and cognitive impairment. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic adrenomedullary system, which are regulated by neuronal pathways, including the inhibitory GABAergic (gamma-aminobutyric acid) system. Approximately 60% of the variance in glucocorticod levels may be attributable to genetic individual differences. In the present study, 56 healthy subjects underwent genotyping to determine the influence of the T1521C single nucleotide polymorphism (SNP) in the GABA(A)alpha6 receptor subunit gene (GABRA6) on the hormonal and autonomic responses to psychological stress induced by the Trier Social Stress Test (TSST). Adrenocorticotropin (ACTH), cortisol, diastolic blood pressure, and mean blood pressure responses to the TSST were significantly greater in subjects homozygous for the T allele or heterozygous compared to subjects homozygous for the C allele. Behavioral data was collected employing the Revised NEO Personality Inventory (NEO PI-R); subjects homozygous for the C allele scored significantly lower on the Extraversion factor compared to subjects homozygous for the T allele or heterozygous. These results suggest that the T1521C polymorphism in the GABRA6 gene is associated with specific personality characteristics as well as a marked attenuation in hormonal and blood pressure responses to psychological stress.
Asunto(s)
Hidrocortisona/sangre , Personalidad/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de GABA-A/genética , Estrés Psicológico/sangre , Estrés Psicológico/genética , Hormona Adrenocorticotrópica/sangre , Adulto , Sustitución de Aminoácidos/genética , Presión Sanguínea/genética , Femenino , Frecuencia de los Genes , Homocigoto , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Sistema Hipófiso-Suprarrenal/fisiopatología , Subunidades de Proteína/genética , Valores de ReferenciaRESUMEN
Although far from conclusive, evidence implicating the endogenous opioid system in the development and maintenance of alcoholism is growing. Currently available data suggest that ethanol increases opioid neurotransmission and that this activation is part of the mechanism responsible for its reinforcing effects. Findings from preclinical research indicate that ethanol consumption and ethanol-induced dopamine (DA) release are both reduced by opioid antagonists. Individual differences in endogenous opioid activity have been linked to inherited risks for alcoholism in studies comparing ethanol-preferring and nonpreferring rats, as well as in studies using targeted gene mutation (knockout) strategies. To a large extent, findings from human studies have paralleled those from the preclinical work. Persons who differ in family history of alcoholism have been shown to also differ in basal beta-endorphin activity, beta-endorphin response to alcohol, and subjective and HPA axis hormonal response to opioid antagonists. Findings from clinical trials indicate that opioid antagonists may reduce ethanol consumption in alcoholics, particularly in persons who have resumed drinking. Nevertheless, many questions remain unanswered about the use of opioid antagonists in alcoholism treatment and about the exact role of the opioid system in ethanol preference and reward. The progression of knowledge in this field suggests that many of these questions are imminently answerable, as our ability to characterize relationships between opioid activity and human behavior continues to develop. This paper summarizes both the progress that has been made and the gaps that remain in our understanding of the interactions between the endogenous opioid system and risk for alcoholism.
Asunto(s)
Alcoholismo/etiología , Endorfinas/metabolismo , Consumo de Bebidas Alcohólicas/fisiopatología , Alcoholismo/tratamiento farmacológico , Alcoholismo/genética , Animales , Endorfinas/genética , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Sistema Hipófiso-Suprarrenal/fisiopatología , Receptores Opioides/metabolismo , Recompensa , Factores de Riesgo , Estrés Fisiológico/fisiopatología , Transmisión SinápticaRESUMEN
The functional consequences of the age-associated decline in IGF-I are unknown. We hypothesized that low IGF-I levels in older women would be associated with poor muscle strength and mobility. We assessed this question in a population representative of the full spectrum of health in the community, obtaining serum IGF-I levels from women aged 70-79 yr, enrolled in the Women's Health and Aging Study I or II. Cross-sectional analyses were performed using 617 women with IGF-I levels drawn within 90 d of measurement of outcomes. After adjustment for age, there was an association between IGF-I and knee extensor strength (P = 0.004), but not anthropometry or other strength measures. We found a positive relationship between IGF-I levels and walking speed for IGF-I levels below 50 microg/liter (P < 0.001), but no relationship above this threshold. A decline in IGF-I level was associated with self-reported difficulty in mobility tasks. All findings were attenuated after multivariate adjustment. In summary, in a study population including frail and healthy older women, low IGF-I levels were associated with poor knee extensor muscle strength, slow walking speed, and self-reported difficulty with mobility tasks. These findings suggest a role for IGF-I in disability as well as a potential target population for interventions to raise IGF-I levels.
Asunto(s)
Factor I del Crecimiento Similar a la Insulina/metabolismo , Músculo Esquelético/fisiología , Actividades Cotidianas , Anciano , Envejecimiento/fisiología , Composición Corporal/fisiología , Peso Corporal/fisiología , Estudios Transversales , Femenino , Fuerza de la Mano/fisiología , Hormona de Crecimiento Humana/sangre , Humanos , Flebotomía , Desempeño Psicomotor/fisiologíaRESUMEN
Alcohol ingestion activates the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. This study examined naltrexone effects on alcohol-induced increases in physiological responses and their association with alcohol liking. Using a within-subjects design, heavy drinking men (N = 19) were maintained on each of three naltrexone doses (0, 50, and 100 mg, p.o.) over an 8-day inpatient stay. Within each naltrexone dose, subjects had three alcohol challenge sessions (none, moderate, high) in random order. Autonomic, subjective and endocrine measurements were collected regularly prior to and following alcohol administration. High-dose alcohol ingestion increased heart rate, diastolic blood pressure, skin temperature, ACTH, cortisol and liking of drink effects; responses following the moderate alcohol dose were less consistent. Naltrexone significantly dampened alcohol-induced increases in heart rate, diastolic blood pressure, hormone levels and subjective liking of drink effects. This dampening of cardiovascular and hormonal responses may contribute to the therapeutic effectiveness of naltrexone for reducing alcohol liking and decreasing relapse in alcohol-dependent persons.
Asunto(s)
Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Hemodinámica/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Sistema Hipófiso-Suprarrenal/fisiología , Adulto , Consumo de Bebidas Alcohólicas/psicología , Presión Sanguínea/efectos de los fármacos , Depresores del Sistema Nervioso Central/sangre , Interacciones Farmacológicas , Etanol/sangre , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hormonas/sangre , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Temperatura Cutánea/efectos de los fármacosRESUMEN
BACKGROUND: This study was designed to confirm our previous findings that nonalcoholic offspring from families with alcohol-dependent individuals have greater hypothalamic-pituitary-adrenal axis activation induced by opioid blockade compared with nonalcoholic subjects without a family history of alcohol dependence. METHODS: Sixty-four nonalcoholic subjects aged 18 to 25 years were enrolled in the protocol. Twenty-seven subjects were offspring from families with alcohol dependence and were designated as family history-positive subjects (FHP). Thirty-seven subjects were biological offspring of non-alcohol-dependent parents and were designated as family history-negative subjects (FHN). Subjects received naloxone hydrochloride (0, 50, 125, 375, and 500 microg/kg) in double-blind, randomized order; adrenocorticotropin (ACTH) and cortisol were monitored over 120 min. RESULTS: No hormone differences at baseline or during placebo administration were identified between FHP and FHN subjects. FHP subjects had greater ACTH and cortisol response to opioid receptor blockade induced by naloxone hydrochloride compared with FHN subjects. CONCLUSIONS: These observations confirm previous findings that differences in ACTH and cortisol dynamics between FHP and FHN subjects can be unmasked by opioid receptor blockade.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Alcoholismo/genética , Hipotálamo/efectos de los fármacos , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Hipófisis/efectos de los fármacos , Adolescente , Glándulas Suprarrenales/fisiopatología , Hormona Adrenocorticotrópica/sangre , Adulto , Alcoholismo/fisiopatología , Método Doble Ciego , Femenino , Humanos , Hidrocortisona/sangre , Hipotálamo/fisiopatología , Masculino , Naloxona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Hipófisis/fisiopatología , PlacebosRESUMEN
Ethanol and other drugs of abuse modulate cAMP-PKA signaling within the mesolimbic reward pathway. To understand the role of the cAMP-PKA signal transduction in mediating the effects of ethanol, we have studied ethanol consumption and the sedative effects of ethanol in three lines of genetically modified mice. We report that mice with the targeted disruption of one Gsalpha allele as well as mice with reduced neuronal PKA activity have decreased alcohol consumption compared with their wild-type littermates. Genetic reduction of cAMP-PKA signaling also makes mice more sensitive to the sedative effects of ethanol, although plasma ethanol concentrations are unaffected. In contrast, mice with increased adenylyl cyclase activity resulting from the transgenic expression of a constitutively active form of Gsalpha in neurons within the forebrain are less sensitive to the sedative effects of ethanol. Thus, the cAMP-PKA signal transduction pathway is critical in modulating sensitivity to the sedative effects of ethanol as well as influencing alcohol consumption.
Asunto(s)
Consumo de Bebidas Alcohólicas/metabolismo , Depresores del Sistema Nervioso Central/administración & dosificación , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Etanol/administración & dosificación , Subunidades alfa de la Proteína de Unión al GTP Gs , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Proteínas del Tejido Nervioso , Transducción de Señal/fisiología , Adenilil Ciclasas/metabolismo , Consumo de Bebidas Alcohólicas/genética , Alelos , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Quimera , Conducta de Elección/efectos de los fármacos , Conducta de Elección/fisiología , Cromograninas , Cruzamientos Genéticos , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Resistencia a Medicamentos/genética , Etanol/sangre , Femenino , Predisposición Genética a la Enfermedad , Proteínas de Unión al GTP Heterotriméricas/genética , Heterocigoto , Masculino , Ratones , Ratones Endogámicos C57BL , Autoadministración , Transducción de Señal/efectos de los fármacos , Sueño/efectos de los fármacosRESUMEN
Addison's crisis is the most serious complication of adrenal insufficiency. To elucidate the mechanism of this disorder following infection, the role of TNF in adrenalectomized murine models of Addison's crisis and Addison's disease (chronic hypoglucocorticoidism) were examined. Adrenalectomy conferred a 40-fold increased sensitivity to the lethal effects of lipopolysacharride (LPS) (P < .001). Enhanced sensitivity to LPS was found to increase with duration of adrenal insufficiency (P < .02). Enhanced lethality to heat-killed Streptococcus pneumonia was also demonstrated (P < 0.02). Necropsy of endotoxin-killed adrenalectomized mice demonstrated similar pathologic findings to those found by others when the control mice were administered a lethal dose of either LPS or TNF. Adrenalectomized TNF receptor Ia and Ib double null mice were demonstrated to be resistant to the lethal effects of LPS (P < 0.02). Pretreatment with anti-TNF, but not control antisera, was found to prevent death in LPS-treated wild-type adrenalectomized mice as well (P < 0.02). Studies into the mechanism by which TNF was precipitating Addison's crisis demonstrated enhanced sensitivity to TNF (3-fold; P < 0.02), and a marked increase in serum TNF concentration (approximately 5-fold; P < 0.001) following LPS challenge. The effect of TNF upon long-term survival in adrenalectomized mice was examined in TNF-receptor Ia- and Ib-deficient mice. Deficiencies in either the TNF-receptor Ia or Ib was noted to confer a survival advantage relative to colony controls following adrenalectomy (P < 0.02). In summary, both LPS-induced Addison's crisis and chronic adrenal insufficiency are disorders of TNF disregulation. Based upon these data, therapeutic strategies targeted at controlling TNF in adrenal insufficiency are suggested.
Asunto(s)
Enfermedad de Addison/fisiopatología , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedad de Addison/metabolismo , Enfermedad de Addison/mortalidad , Adrenalectomía/efectos adversos , Animales , Antígenos CD , Modelos Animales de Enfermedad , Endotoxinas , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos , Receptores del Factor de Necrosis Tumoral/deficiencia , Receptores Tipo I de Factores de Necrosis Tumoral , Receptores Tipo II del Factor de Necrosis Tumoral , Streptococcus pneumoniae , Tasa de Supervivencia , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
BACKGROUND: There is strong evidence for the role of the endogenous opioid system in alcohol reinforcement and consumption; however, recent human laboratory studies and clinical trials have reported mixed effects of naltrexone (a nonselective opioid antagonist) on alcohol-related behaviors. This paper reports a secondary data analysis of a human laboratory study that examines the relationship between serum levels of 6-beta-naltrexol, the major, biologically active metabolite of naltrexone, and subjective effects of alcohol. METHODS: The study used a within-subjects design to examine the effects of naltrexone (0, 50, and 100 mg/day) on subjective responses to alcohol (none, moderate, and high dose) in heavy drinkers (n = 23). Each subject received three doses of naltrexone in random order; each naltrexone dose was administered over an 8 day period on an inpatient unit, with a 1 week outpatient washout between doses. After stabilization at each of the naltrexone doses, subjects participated in three alcohol challenge sessions (none, moderate, and high dose) in random order; thus, each subject participated in a total of nine alcohol administration sessions. RESULTS: Doubling the naltrexone dose (50 vs. 100 mg/day) doubled the mean serum 6-beta-naltrexol levels. At each naltrexone dose, there was a 4-fold range in 6-beta-naltrexol levels across subjects. Before alcohol administration, higher 6-beta-naltrexol levels were associated with higher ratings of sedation. After high-dose alcohol administration, higher 6-beta-naltrexol levels were associated with significantly lower ratings of liking and best effects. CONCLUSIONS: These findings provide further evidence of the involvement of the opioid system in the modulation of alcohol effects and suggest that serum 6-beta-naltrexol concentrations may be important in predicting therapeutic response to naltrexone.
Asunto(s)
Afecto/efectos de los fármacos , Consumo de Bebidas Alcohólicas/sangre , Alcoholismo/sangre , Naltrexona/análogos & derivados , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Adulto , Afecto/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Naltrexona/sangre , Naltrexona/metabolismo , Antagonistas de Narcóticos/metabolismoRESUMEN
Although nonsecreting suprarenal embryonic remnants are frequently found in the urogenital tract, adenomatous transformation resulting in glucocorticoid excess is a rare phenomenon. We report a case of a 63-yr-old woman that presented with new-onset hirsutism, facial plethora, hypertension, centripetal obesity, and a proximal myopathy. The 24-h urinary free cortisol excretion rate was elevated, and the serum ACTH level was suppressed. The patient failed an overnight and low dose dexamethasone suppression test and did not respond to CRH stimulation. In light of the undetectable baseline morning ACTH levels and the blunt response to CRH, the diagnosis of corticotropin-independent Cushing's syndrome was made. Imaging studies revealed normal adrenal glands and enlargement of a left pararenal nodule incidentally observed 4 yr before the onset of symptoms. Dramatic resolution of symptoms was observed after surgical removal of the 3.5-cm mass. Pathological exam confirmed adrenocortical adenoma in ectopic adrenal tissue. The case reported here represents the unusual circumstance in which the development of adenomatous transformation of ectopic adrenal tissue has been prospectively observed with imaging studies. It illustrates the importance of considering ectopic corticosteroid-secreting tumors in the context of corticotropin-independent Cushing's syndrome.
Asunto(s)
Adenoma/diagnóstico , Neoplasias de la Corteza Suprarrenal/diagnóstico , Corteza Suprarrenal , Hormona Adrenocorticotrópica/sangre , Coristoma/diagnóstico , Síndrome de Cushing/etiología , Enfermedades Renales/diagnóstico , Adenoma/diagnóstico por imagen , Adenoma/patología , Adenoma/cirugía , Neoplasias de la Corteza Suprarrenal/diagnóstico por imagen , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/cirugía , Coristoma/patología , Hormona Liberadora de Corticotropina , Dexametasona , Femenino , Hirsutismo , Humanos , Hidrocortisona/orina , Hipertensión , Enfermedades Renales/patología , Persona de Mediana Edad , Obesidad , Tomografía Computarizada por Rayos XRESUMEN
We examined two methods of generating a dose-response curve to the opioid receptor antagonist naloxone. In 15 healthy male subjects (18-25 years) plasma adrenocorticotropin (ACTH) responses to five doses of naloxone studied over 5 separate days were compared to plasma ACTH responses to five incremental doses of naloxone studied within a single session. There was a statistically significant positive correlation in ACTH responses (area under the curve and peak) between dosing methods. Furthermore, the doses of naloxone that produced half-maximal and maximal ACTH response were similar. The comparability of ACTH responses between the two naloxone dosing techniques, combined with the safety and ease associated with the single-session methodology, underscores the usefulness of the single-session technique for future investigations.
Asunto(s)
Hormona Adrenocorticotrópica/sangre , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Adolescente , Hormona Adrenocorticotrópica/metabolismo , Adulto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Masculino , Naloxona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Distribución AleatoriaRESUMEN
BACKGROUND: Previous in vivo studies show that acute ethanol exposure sequentially increases protein kinase A (PKA) activity, the phosphorylation of the adenosine 3':5'-cyclic monophosphate (cAMP)-dependent transcription factor, CREB, and finally proenkephalin gene expression. The present study was conducted to determine if ethanol could activate directly the adenylyl cyclase pathway and thus enhance proenkephalin promoter activity. METHODS: Cultured rat C6 glioma cells stably transfected with a segment of the five prime flanking region of rat proenkephalin promoter (nucleotide -2700+/-53) ligated to the chloramphenicol acetyltransferase (CAT) reporter gene were employed to study the effects of ethanol on proenkephalin promoter activity. This region of proenkephalin promoter contains two cAMP response elements (CRE-1 and CRE-2) and one AP2 site located in the region upstream of the TATA box. Cultures were exposed to ethanol, isoproterenol, and phorbol-12, myristate 13-acetate (PMA) alone and in combination, in the presence and absence of PKA and protein kinase C (PKC) inhibitors. RESULTS: Ethanol and isoproterenol increased proenkephalin promoter activity in a dose-dependent manner. Ethanol had an additive effect on maximal isoproterenol-stimulated proenkephalin promoter activity, which suggested that ethanol used a cAMP-independent signal transduction pathway to increase proenkephalin promoter activation. In contrast with isoproterenol, ethanol exposure did not increase cAMP accumulation, PKA activity, or the phosphorylated form of CREB. However, ethanol exposure modestly increased PKC activity. The PKA-specific inhibitor, Rp-cAMP, dampened isoproterenol-induced activation of CAT activity but did not alter ethanol's ability to increase CAT activity. However, the PKC inhibitors, chelerthyrine and G07874, abrogated ethanol's effect of CAT activity but did not alter isoproterenol's effects. CONCLUSIONS: Ethanol enhanced proenkephalin promoter activity and potentiated isoproterenol-stimulated promoter activity through a cAMP-independent pathway.
Asunto(s)
Depresores del Sistema Nervioso Central/farmacología , Colina O-Acetiltransferasa/efectos de los fármacos , AMP Cíclico/metabolismo , Encefalinas/efectos de los fármacos , Etanol/farmacología , Precursores de Proteínas/efectos de los fármacos , Agonistas Adrenérgicos beta/farmacología , Animales , Colina O-Acetiltransferasa/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Encefalinas/metabolismo , Inhibidores Enzimáticos/farmacología , Glioma/metabolismo , Isoproterenol/farmacología , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/fisiología , Proteína Quinasa C/antagonistas & inhibidores , Precursores de Proteínas/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Células Tumorales CultivadasRESUMEN
Endogenous opioid activity has been associated with the regulation of mood and inhibition of the hypothalamic-pituitary-adrenal (HPA) axis. We assessed differences in psychological symptomology and naloxone sensitivity in non-alcoholic males and females with a family history of alcoholism (FHP) and without a family history of alcoholism (FHN). This was followed by assessment of the association between naloxone sensitivity and psychological symptomology. Psychological symptomology was measured using the Revised Symptom Checklist (SCL-90-R) during enrollment. Adrenocorticotropin was measured following intravenous administration of naloxone/placebo. FHP males reported more obsessive-compulsive symptomology as well as increased sensitivity to naloxone relative to other groups. A positive association was observed between degree of obsessive-compulsive symptomology and naloxone sensitivity, and the association was strongest among FHP males. These findings suggest that the increased risk of alcoholism in FHP subjects (especially males) may be associated with altered opioid activity, which is expressed through an elevated level of obsessive compulsive symptomology.
Asunto(s)
Alcoholismo/genética , Alcoholismo/psicología , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/psicología , Péptidos Opioides/fisiología , Adolescente , Hormona Adrenocorticotrópica/fisiología , Adulto , Distribución por Edad , Alcoholismo/fisiopatología , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Trastorno Obsesivo Compulsivo/fisiopatología , Escalas de Valoración Psiquiátrica , Distribución por Sexo , Factores de TiempoRESUMEN
Preclinical studies support endogenous opioid system involvement in alcohol reinforcement and consumption; however, recent clinical trials and human laboratory studies have provided mixed findings of the effects of naltrexone (a non-selective opioid antagonist) on alcohol responses. This study used a within-subject design (n = 23) to investigate naltrexone effects (0, 50 and 100 mg qd) on subjective and psychomotor responses to alcohol (none, moderate, high) in heavy drinkers. Before alcohol administration, subjects reported decreased desire to drink alcohol when maintained on 50 mg compared with placebo naltrexone. Following alcohol administration, active naltrexone significantly increased subjective ratings of sedative, and unpleasant/sick effects and decreased ratings of liking, best effects and desire to drink. Naltrexone generally did not alter subjective or objective indicators of drunkenness. Finally, high doses of naltrexone and alcohol interacted to produce the greatest decreases in liking and best effects. Findings support the role of endogenous opioids as determinants of alcohol's effects and suggest that naltrexone may be particularly clinically useful in those treatment patients who continue to drink heavily.
Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/fisiopatología , Etanol/administración & dosificación , Etanol/efectos adversos , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Adulto , Relación Dosis-Respuesta a Droga , Etanol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Naltrexona/efectos adversos , Antagonistas de Narcóticos/efectos adversos , Factores de TiempoRESUMEN
BACKGROUND: This study was designed to assess whether nonalcoholic offspring from families with a high density of alcohol-dependent individuals have altered hypothalamic-pituitary-adrenal (HPA) axis dynamics compared with nonalcoholic subjects without a family history of alcohol dependence. METHODS: Seventy-eight nonalcoholic subjects aged 18 to 25 were enrolled in the protocol. Thirty-nine subjects were offspring from families with a high density of alcohol dependence and were designated as family history-positive (FHP) subjects. Thirty-nine subjects were biological offspring of nonalcohol-dependent parents and were designated as family history-negative (FHN) subjects. Subjects received naloxone hydrochloride (0 and 125 microg/kg) and cosyntropin (0, 0.25 microg, and 250 microg) in double-blind, randomized order and cortisol was monitored. A subset of subjects (11 FHP, 11 FHN) was admitted to the General Clinical Research Center to measure serum cortisol levels every 30 min for 24 hr. RESULTS: FHP subjects had an increased cortisol response to opioid receptor blockade induced by naloxone. However, no group differences in cortisol were uncovered during administration of cosyntropin or during monitoring of the cortisol circadian profile. CONCLUSION: These observations suggest that differences in the cortisol dynamics between FHP and FHN subjects are unmasked by opioid receptor blockade directed at the hypothalamus, but not when cortisol levels are directly provoked at the level of the adrenal gland. In addition, unprovoked cortisol secretion monitored over a 24-hr interval cannot distinguish FHP from FHN subjects.
Asunto(s)
Alcoholismo/sangre , Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Adolescente , Adulto , Alcoholismo/genética , Biomarcadores/sangre , Ritmo Circadiano , Cosintropina , Método Doble Ciego , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Naloxona , Antagonistas de Narcóticos , Sistema Hipófiso-Suprarrenal/efectos de los fármacosRESUMEN
The endogenous opioid system is part of a neural circuitry functionally related to alcohol-seeking behaviors. A family history of alcoholism is the strongest predictor of future development of alcohol dependence. This study was designed to evaluate ACTH responses to opioid receptor blockade as a function of family history for alcohol dependence. The nonselective opioid antagonist naloxone stimulates ACTH secretion by blocking opioidergic input on paraventricular corticotropin-releasing factor neurons, thereby providing a methodology for comparing hypothalamic opioid tone between study groups. Sixty nonalcoholic subjects, aged 18-25 yr, were enrolled in a protocol to measure the ACTH response to naloxone. Thirty-two subjects were offspring from families with a high density of alcohol dependence and were designated as family history-positive subjects. Twenty-eight subjects were offspring of nonalcohol-dependent parents and were designated family history-negative subjects. Subjects received naloxone (125 microg/kg) or placebo (0.9% saline) in double blind, randomized order. Plasma ACTH was monitored. Family history-positive men had increased ACTH response to naloxone compared to 1) family history-positive women, 2) family history-negative men, and 3) family history-negative women. Despite differences in plasma ACTH levels after naloxone administration, plasma naloxone concentrations did not differ between study groups. This finding suggests that nonalcoholic male offspring of alcohol-dependent men have altered endogenous opioid activity directed at hypothalamic corticotropin-releasing factor neurons.
Asunto(s)
Hormona Adrenocorticotrópica/sangre , Alcoholismo/genética , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Adolescente , Adulto , Alcoholismo/sangre , Hormona Liberadora de Corticotropina/metabolismo , Método Doble Ciego , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Sistema Hipófiso-Suprarrenal/fisiologíaRESUMEN
BACKGROUND: This study was designed to assess whether nonalcoholic offspring from families with a high density of alcohol-dependent individuals have altered endogenous central nervous system opioid activity. Naloxone hydrochloride stimulates plasma cortisol by blocking opioidergic input on the corticotropin-releasing factor neuron, thereby providing a noninvasive method for measuring hypothalamic opioid tone. METHODS: Forty-eight nonalcoholic subjects aged 18 to 25 years were enrolled in a protocol to measure endogenous opioid activity by inducing opioid receptor blockade with the receptor antagonist, naloxone. Twenty-six subjects were offspring from families with a high density of alcohol dependence and were designated as family history-positive subjects. Twenty-two subjects were biological offspring of nonalcohol-dependent parents and designated as family history-negative subjects. Subjects received naloxone hydrochloride (0, 125, and 375 microg/kg) in double-blind, randomized order. Serum cortisol levels were monitored. RESULTS: Family history-negative subjects had a graded cortisol response to each dose of naloxone. In contrast, family history-positive subjects achieved a maximal cortisol response to the 125-microg/kg dose of naloxone hydrochloride with no further increase in cortisol levels observed following the 375-microg/kg dose. Family history-negative subjects had a diminished cortisol response to the 125-microg/kg dose compared with the family history-positive subjects. Plasma naloxone concentrations did not differ between family history groups. CONCLUSIONS: Individuals from families with a high density of alcohol dependence are more sensitive to naloxone compared with offspring of nonalcohol-dependent parents. This implies that individuals with a family history of alcohol dependence have diminished endogenous hypothalamic opioid activity.
Asunto(s)
Alcoholismo/genética , Familia , Hipotálamo/química , Péptidos Opioides/análisis , Adolescente , Adulto , Alcoholismo/diagnóstico , Alcoholismo/epidemiología , Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Hidrocortisona/sangre , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiología , Masculino , Naloxona/sangre , Naloxona/farmacología , Péptidos Opioides/antagonistas & inhibidores , Receptores Opioides/efectos de los fármacosRESUMEN
The purpose of the present study was to further the understanding of the relationship between plasma leptin concentrations, hypothalamic opioid tone, and plasma ACTH secretory dynamics. ACTH(1-24) challenges (250 micrograms) produced the expected increase in plasma cortisol levels but did not alter plasma leptin levels. Activation of the entire hypothalamic-pituitary-adrenal (HPA) axis was induced by employing the opioid receptor antagonist, naloxone. By blocking opioidergic inhibitory input to hypothalamic CRH neurons, naloxone induced the expected increase in plasma ACTH and cortisol. Plasma ACTH levels peaked 30 min after naloxone administration, whereas plasma cortisol levels peaked 60 min after opioid receptor blockade. Once again, plasma leptin concentrations were not altered by this manipulation. However, there was a positive correlation between fasting, integrated plasma leptin concentrations, and plasma ACTH responses to naloxone (peak r = 0.822, P < 0.0001; and area under curve r = 0.832, P < 0.0001). The correlation was stronger when leptin was normalized to body mass index and expressed as the leptin/body mass index ratio (peak r = 0.878, P < 0.00001; and area under curve r = 0.882, P < 0.00001). In summary, these findings indicate that activation of the HPA axis does not acutely alter plasma leptin concentrations. However, plasma leptin levels may influence hypothalamic opioidergic tone and thus modulate the magnitude of CRH release. The acute interaction of the HPA axis and leptin is unidirectional.