RESUMO
Corticotropin-releasing factor (CRF) is a potent neuromodulator of stress-related behaviour but the neural mechanisms underlying these effects are not clear. Studies were designed to test the hypothesis that CRF-induced behavioural arousal involves interactions with brainstem serotonergic systems. To examine interactions between CRF and serotonergic systems in the regulation of behaviour, CRF (1 microg, intracerebroventricular (i.c.v.)) or vehicle was infused in the presence or absence of the selective serotonin re-uptake inhibitor fluoxetine (0, 0.1, 1 or 10 mg/kg, intravenous (i.v.)). Fluoxetine was used at these doses because it is known to decrease serotonin cell firing rates while increasing extracellular serotonin concentrations in select forebrain regions. We then measured behavioural, neurochemical and endocrine responses. CRF increased locomotion and spontaneous non-ambulatory motor activity (SNAMA) in the home cages. Fluoxetine decreased tissue 5-hydroxyindoleacetic acid concentrations, a measure of serotonin metabolism, in specific limbic brain regions of CRF-treated rats (nucleus accumbens shell region, entorhinal cortex, central nucleus of the amygdala). Furthermore, fluoxetine inhibited CRF-induced SNAMA. CRF and fluoxetine independently increased plasma corticosterone concentrations, but the responses had distinct temporal profiles. Overall, these data are consistent with the hypothesis that CRF-induced facilitation of behavioural activity is dependent on brainstem serotonergic systems. Therefore, fluoxetine may attenuate or alleviate some behavioural responses to stress by interfering with CRF-induced responses.
Assuntos
Comportamento Animal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/fisiologia , Fluoxetina/farmacologia , Animais , Nível de Alerta/efeitos dos fármacos , Corticosterona/sangue , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Fluoxetina/administração & dosagem , Ácido Hidroxi-Indolacético/metabolismo , Injeções Intraventriculares , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Ratos , Ratos Wistar , Serotonina/metabolismoRESUMO
BACKGROUND: The developmental origins hypothesis suggests that pre- and postnatal exposures may influence vulnerability to later disease. The hypothalamic-pituitary-adrenal (HPA) axis is one pathway by which this may occur. Analyses were conducted in the Barry Caerphilly Growth (BCG) cohort to explore whether the postnatal exposure of childhood infections was related to HPA axis activity in adulthood. METHODS: Detailed data on type and frequency of illnesses were collected in the first 5 years of life. At the recent follow-up of this cohort (N=566; mean age of participants=25 years) three salivary cortisol samples were taken: two fasting samples in the morning (within 30 min of arrival at the study site and after venesection and cognitive test procedures) and one evening sample (2200 h). These data were transformed to provide AUCi and AUCg (indices reflecting axis reactivity and total hormonal output, respectively). FINDINGS: Negative associations were evident between number of upper respiratory illnesses and adult cortisol (as captured by the second morning sample, evening sample and AUCg). These relationships remained after controlling for other potential prenatal, postnatal and adult determinants. These associations were not observed for gastrointestinal illnesses suggesting that confounding by socioeconomic factors is unlikely to be the explanation. CONCLUSIONS: Childhood respiratory illnesses were associated with reduced HPA axis activity in adulthood. Further follow-ups will determine whether this pattern of activity influences vulnerability to diseases associated with HPA regulation.
Assuntos
Desenvolvimento Infantil/fisiologia , Gastroenteropatias/epidemiologia , Hidrocortisona/análise , Doenças Respiratórias/epidemiologia , Adulto , Idade de Início , Área Sob a Curva , Peso ao Nascer/fisiologia , Pré-Escolar , Ritmo Circadiano/fisiologia , Estudos de Coortes , Inglaterra/epidemiologia , Feminino , Seguimentos , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiologia , Estudos Retrospectivos , País de Gales/epidemiologiaRESUMO
We reported previously that the neuropeptide oxytocin attenuates stress-induced hypothalamo-pituitary-adrenal (HPA) activity and anxiety behavior. This study sought to identify forebrain target sites through which oxytocin may mediate its anti-stress effects. Ovariectomized, estradiol-treated rats received intracerebroventricular infusions of oxytocin (1 or 10 ng/hr) or vasopressin (10 ng/hr), and the patterns of neuronal activation after restraint stress were determined by semiquantitative mapping of c-fos mRNA expression. Oxytocin administration significantly attenuated the release of ACTH and corticosterone and the increase in corticotropin-releasing factor mRNA expression in the hypothalamic paraventricular nucleus (PVN) in response to 30 min restraint. Restraint also induced the expression of c-fos mRNA in selective regions of the forebrain, including the PVN, paraventricular thalamic nucleus, habenula, medial amygdala, ventrolateral septum (LSV), most subfields of the dorsal and ventral hippocampus, and piriform and endopiriform cortices. In most cases, this level of gene expression was unaffected by concomitant administration of oxytocin. However, in the PVN, LSV, and throughout all subfields of the dorsal hippocampus, restraint evoked no detectable increase in c-fos mRNA in animals treated with either dose of oxytocin. Vasopressin had no effects on either HPA axis responses or neuronal activation in response to restraint, indicating that the effects were highly peptide selective. These data show that central oxytocin attenuates both the stress-induced neuroendocrine and molecular responses of the HPA axis and that the dorsal hippocampus, LSV, and PVN constitute an oxytocin-sensitive forebrain stress circuit.
Assuntos
Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Ocitocina/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Prosencéfalo/metabolismo , RNA Mensageiro/metabolismo , Estresse Fisiológico/metabolismo , Animais , Feminino , Expressão Gênica/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Injeções Intraventriculares , Sistema Hipófise-Suprarrenal/fisiologia , Prosencéfalo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Sprague-Dawley , Restrição Física , Estresse Fisiológico/tratamento farmacológicoRESUMO
Alterations in cellular immune function are associated with depression and have been related to changes in endocrine function. We carried out a study to: (i) reliably assess the hypothalamic-pituitary-adrenal (HPA) axis function in treatment resistant depression (TRP); (ii) evaluate whether depression was associated with changes on T-cell proliferation and cytokine production; and (iii) assessed the sensitivity of lymphocytes to glucocorticoids (GC)s in vitro. Thirty-six pharmacologically treated inpatients diagnosed with TRP and 31 healthy controls took part in the study. Salivary cortisol was measured hourly from 0800 to 2200 h both before and after dexamethasone (DEX) intake and the patients were classified into HPA axis suppressors and nonsuppressors. The following were measured in vitro: (a) phytohemagglutinin-induced T-cell proliferation; (b) cytokine production (interleukin-2 and tumor necrosis factor-alpha, TNF-alpha); and (c) lymphocyte sensitivity to both cortisol and DEX. Basal morning cortisol levels from patients and controls did not differ nor did their T-cell proliferation and cytokine production. Ten out of 36 patients were classified as nonsuppressors and presented a significantly higher post-DEX salivary cortisol levels than suppressors, 82.0 vs 8.9 nM/l/h (p <0.001). Cells of nonsuppressors produced significantly less TNF-alpha compared to suppressors, 299.8 vs 516.9 pg/ml (p < 0.05). Remarkably, GC-induced suppression of lymphocyte proliferation and cytokine production were generally less marked in depressives compared with controls. Our data indicate that alterations in immune function and steroid regulation associated with depression are not related to elevated basal levels of cortisol and suggest that lymphocyte steroid resistance may be associated with TRP.
Assuntos
Antidepressivos/uso terapêutico , Depressão/imunologia , Resistência a Medicamentos , Glucocorticoides/farmacologia , Imunidade/efeitos dos fármacos , Glândulas Suprarrenais/efeitos dos fármacos , Adulto , Idoso , Antidepressivos/farmacologia , Células Cultivadas , Citocinas/biossíntese , Depressão/tratamento farmacológico , Dexametasona/administração & dosagem , Feminino , Humanos , Hidrocortisona/análise , Hipotálamo/efeitos dos fármacos , Interleucina-2/biossíntese , Ativação Linfocitária , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fito-Hemaglutininas/farmacologia , Hipófise/efeitos dos fármacos , Saliva/química , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Alterations in immune function are associated with major depression and have been related to changes in endocrine function. We investigated whether alterations in immune function were associated with altered basal hypothalamic-pituitary-adrenal (HPA) function (salivary cortisol) and lymphocyte sensitivity to dexamethasone (DEX) intake (1 mg PO). The latter was explored by comparing the impact of DEX-induced changes on peripheral lymphocyte redistribution and expression of adhesion molecules (beta2 integrins and L-selectin). The study included 36 inpatients with treatment-resistant major depression (unipolar subtype) and 31 matched healthy controls. The dexamethasone suppression test (DST) was carried out and used to classify 10 patients as HPA axis non-suppressors. The latter presented significantly higher post-DEX salivary cortisol levels than DST suppressors, 82.0 vs. 8.9 nM l(-1) h(-1). No differences in basal salivary cortisol levels were found between patients and controls. Changes in cell redistribution (CD4(+), CD8(+), CD19(+), CD56(+) and HLADR(+) cells) after DEX administration were more prominent in controls than in patients, but the effects of DEX varied dependent on whether patients exhibited DEX-induced suppression of cortisol secretion. Glucocorticoid-induced suppression of adhesion molecule expression was also generally less marked in patients than controls. Our data indicate that alterations in immune function and steroid regulation associated with depression are not related to elevated basal levels of cortisol and further suggest that lymphocyte steroid resistance is associated with drug-resistant depression.
Assuntos
Antidepressivos/uso terapêutico , Moléculas de Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Adulto , Idoso , Anticorpos Monoclonais , Antígenos CD19/efeitos dos fármacos , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Antígenos CD4/efeitos dos fármacos , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Antígeno CD56/efeitos dos fármacos , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/imunologia , Antígenos CD8/metabolismo , Transtorno Depressivo Maior/imunologia , Resistência a Medicamentos , Feminino , Antígenos HLA-DR/efeitos dos fármacos , Antígenos HLA-DR/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Hidrocortisona/análise , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Saliva/química , Linfócitos T/imunologiaRESUMO
Early life environmental factors have been associated with altered predisposition to a variety of pathologies. A considerable literature examines pre- and postnatal factors associated with increased risk of cardiovascular, metabolic (i.e. insulin resistance, hyperlipidemia) and psychiatric disease, and the importance of hormonal programming. The brain is exquisitely sensitive to environmental inputs during development and the stress responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to be both up- and down-regulated by early life exposure to limited nutrition, stress, altered maternal behaviors, synthetic steroids and inflammation. It has been suggested that peri-natal programming of HPA axis regulation might therefore contribute to metabolic and psychiatric disease etiology. In addition, glucocorticoids play modulatory roles regulating many aspects of immune function, notably controlling both acute and chronic inflammatory responses. Neuroendocrine-immune communication is bidirectional, and therefore it is expected that environmental factors altering HPA regulation have implications for stress effects on immune function and predisposition to inflammation. The impact of pre- and postnatal factors altering immune function, stress responsivity and predisposition to inflammatory disease are reviewed. It is also examined whether the early 'immune environment' might similarly influence predisposition to disease and alter neuroendocrine function. Evidence indicating a role for early life inflammation and infection as an important factor programming the neuroendocrine-immune axis and altering predisposition to disease is considered.
RESUMO
Conventional cardiovascular risk factors such as cholesterol and blood pressure do not account fully for variation in coronary heart disease suggesting the involvement of additional mechanisms. We have examined the effects of a chronic psychological stress protocol on the development of atherosclerosis in the apolipoprotein E knockout mouse. We observed a 3-fold increase in staining for atheroma accompanied by a 10-fold increase in corticosterone concentrations in mice stressed for 12 weeks. These data suggest that chronic mild stress can induce or accelerate the development of atherosclerosis.
Assuntos
Apolipoproteínas E/deficiência , Arteriosclerose/etiologia , Estresse Psicológico/complicações , Animais , Doença Crônica , Feminino , Masculino , Camundongos , Camundongos Knockout , Odorantes , Ratos/metabolismo , Estresse Psicológico/etiologia , Fatores de TempoRESUMO
The dorsomedial hypothalamus (DMH) plays an important role in relaying information to neural pathways mediating neuroendocrine, autonomic, and behavioral responses to stress. Evidence suggests that the DMH is a structurally and functionally diverse integrative structure that contributes to both facilitation and inhibition of the hypothalamo-pituitary-adrenal axis, depending on the nature of the stimulus and the specific neural circuits involved. Previous studies have determined that stress or stress-related stimuli elevate tissue concentrations of serotonin (5-hydroxytryptamine; 5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine, and noradrenaline selectively within the DMH. In order to determine the specific region of the rat DMH involved, we used high-performance liquid chromatography with electrochemical detection to measure tissue concentrations of 5-HT, 5-HIAA, dopamine, and noradrenaline within five different subregions of the DMH in adult female Lewis and Fischer rats immediately or 4 h following a 30-min period of restraint stress. Compared to unrestrained control rats, restrained rats had elevated concentrations of 5-HT, 5-HIAA, dopamine, and noradrenaline immediately after a 30-min period of restraint and had elevated concentrations of 5-HT 4 h following the onset of a 30-min period of restraint stress. These effects were confined to a specific region that included medial portions of the dorsal hypothalamic area and dorsal ependymal, subependymal, and neuronal components of the periventricular nucleus. Furthermore, these effects were observed in Lewis rats, but not Fischer rats, two closely related rat strains with well-documented differences in neurochemical, neuroendocrine, autonomic, and behavioral responses to stress. These data provide support for the existence of a stress-responsive, amine-accumulating area in the DMH that may play an important role in the differential stress responsiveness of Lewis and Fischer rats.
Assuntos
Núcleo Hipotalâmico Dorsomedial/anatomia & histologia , Núcleo Hipotalâmico Dorsomedial/metabolismo , Estresse Fisiológico/fisiopatologia , Fatores Etários , Animais , Corticosterona/sangue , Dopamina/metabolismo , Feminino , Ácido Hidroxi-Indolacético/metabolismo , Norepinefrina/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Serotonina/metabolismo , Especificidade da EspécieRESUMO
BACKGROUND: Previous research has demonstrated that the psychological morbidity experienced by informal caregivers is associated with increased vulnerability to infectious diseases, in particular influenza. A pragmatic trial was conducted to examine whether a stress management intervention (SMI) could reduce psychological morbidity and enhance the antibody response to influenza vaccination in the elderly, and whether changes in immune response of SMI participants were associated with hypothalamic-pituitary-adrenal (HPA) axis activity. METHODS: Forty-three elderly spousal carers of dementia patients and 27 non-carer controls were recruited. Sixteen carers were allocated to an 8-week SMI or a non-intervention condition (n = 27). The non-carers formed a no treatment, 'normal' comparison group. At the end of the SMI or its equivalent time period, all participants received an influenza vaccination. IgG antibody titres to the vaccine were measured 0, 2, 4 and 6 weeks post-vaccine. RESULTS: There was evidence of elevated distress in both carer groups compared with non-carer controls throughout the SMI period, but no between-group differences in salivary cortisol. Immune responses to the vaccine revealed that 50% of SMI carers, 7% of non-intervention carers and 29% of non-carer controls produced a four-fold increase in antibody titre. CONCLUSIONS: The immune response to influenza vaccination appears amenable to improvement through stress management, although the mechanisms underlying this effect remain unclear.