Mifepristone in the central nucleus of the amygdala reduces yohimbine stress-induced reinstatement of ethanol-seeking

Chronic ethanol exposure leads to dysregulation of the hypothalamic-pituitary-adrenal axis, leading to changes in glucocorticoid release and function that have been proposed to maintain pathological alcohol consumption and increase vulnerability to relapse during abstinence. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, plays a role in ethanol self-administration and reinstatement. Male, Long-Evans rats were trained to self-administer either ethanol or sucrose in daily 30 min operant self-administration sessions using a fixed ratio 3 schedule of reinforcement. Following establishment of stable baseline responding, we examined the effects of mifepristone on maintained responding and yohimbine-induced increases in responding for ethanol and sucrose. Lever responding was extinguished in separate groups of rats and animals were tested for yohimbine-induced reinstatement and corticosterone release. We also investigated the effects of local mifepristone infusions into the central amygdala (CeA) on yohimbine-induced reinstatement of ethanol- and sucrose-seeking. In addition, we infused mifepristone into the basolateral amygdala (BLA) in ethanol-seeking animals as an anatomical control. We show that both systemic and intra-CeA (but not BLA) mifepristone administration suppressed yohimbine-induced reinstatement of ethanol-seeking, while only systemic injections attenuated sucrose-seeking. In contrast, baseline consumption, yohimbine-induced increases in responding, and circulating CORT levels were unaffected. The data indicate that the CeA plays an important role in the effects of mifepristone on yohimbine-induced reinstatement of ethanol-seeking. Mifepristone may be a valuable pharmacotherapeutic strategy for preventing relapse to alcohol use disorders and, as it is FDA approved, may be a candidate for clinical trials in the near future.

Importance of the central nucleus of the amygdala on sodium intake caused by deactivation of lateral parabrachial nucleus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Involvement of the basolateral complex and central nucleus of amygdala in the omission effects of different magnitudes of reinforcement

Evidence from appetitive Pavlovian and instrumental conditioning studies suggest that the amygdala is involved in modulation of responses correlated with motivational states, and therefore, to the modulation of processes probably underlying reinforcement omission effects. The present study aimed to clarify whether or not the mechanisms related to reinforcement omission effects of different magnitudes depend on basolateral complex and central nucleus of amygdala. Rats were trained on a fixed-interval 12 s with limited hold 6 s signaled schedule in which correct responses were always followed by one of two reinforcement magnitudes. Bilateral lesions of the basolateral complex and central nucleus were made after acquisition of stable performance. After postoperative recovery, the training was changed from 100% to 50% reinforcement schedules. The results showed that lesions of the basolateral complex and central nucleus did not eliminate or reduce, but interfere with reinforcement omission effects. The response from rats of both the basolateral complex and central nucleus lesioned group was higher relative to that of the rats of their respective sham-lesioned groups after reinforcement omission. Thus, the lesioned rats were more sensitive to the omission effect. Moreover, the basolateral complex lesions prevented the magnitude effect on reinforcement omission effects. Basolateral complex lesioned rats showed no differential performance following omission of larger and smaller reinforcement magnitude. Thus, the basolateral complex is involved in incentive processes relative to omission of different reinforcement magnitudes. Therefore, it is possible that reinforcement omission effects are modulated by brain circuitry which involves amygdala. (C) 2012 Elsevier B.V. All rights reserved.

Hepatic-portal vein infusions of glucagon-like peptide-1 reduce meal size and increase c-Fos expression in the nucleus tractus solitarii, area postrema and central nucleus of the amygdala in rats

We recently reported that brief, remotely controlled intrameal hepatic-portal vein infusions of glucagon-like peptide-1 (GLP-1) reduced spontaneous meal size in rats. To investigate the neurobehavioural correlates of this effect, we equipped male Sprague-Dawley rats with hepatic-portal vein catheters and assessed (i) the effect on eating of remotely triggered infusions of GLP-1 (1 nmol/kg, 5 min) or vehicle during the first nocturnal meal after 3 h of food deprivation and (ii) the effect of identical infusions performed at dark onset on c-Fos expression in several brain areas involved in the control of eating. GLP-1 reduced (P < 0.05) the size of the first nocturnal meal and increased its satiety ratio. Also, GLP-1 increased (P < 0.05) the number of c-Fos-expressing cells in the nucleus tractus solitarii, the area postrema and the central nucleus of the amygdala, but not in the arcuate or paraventricular hypothalamic nuclei. These data suggest that the nucleus tractus solitarii, the area postrema and the central nucleus of the amygdala play a role in the eating-inhibitory actions of GLP-1 infused into the hepatic-portal vein; it remains to be established whether activation of these brain nuclei reflect satiation, aversion, or both.

Lesions in the central amygdala impair sodium intake induced by the blockade of the lateral parabrachial nucleus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Lateral parabrachial nucleus and central amygdala in the control of sodium intake

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus

The bed nucleus of the stria terminalis (BNST) is believed to be a critical relay between the central nucleus of the amygdala (CE) and the paraventricular nucleus of the hypothalamus in the control of hypothalamic–pituitary– adrenal (HPA) responses elicited by conditioned fear stimuli. If correct, lesions of CE or BNST should block expression of HPA responses elicited by either a specific conditioned fear cue or a conditioned context. To test this, rats were subjected to cued (tone) or contextual classical fear conditioning. Two days later, electrolytic or sham lesions were placed in CE or BNST. After 5 days, the rats were tested for both behavioral (freezing) and neuroendocrine (corticosterone) responses to tone or contextual cues. CE lesions attenuated conditioned freezing and corticosterone responses to both tone and con- text. In contrast, BNST lesions attenuated these responses to contextual but not tone stimuli. These results suggest CE is indeed an essential output of the amygdala for the expres- sion of conditioned fear responses, including HPA re- sponses, regardless of the nature of the conditioned stimu- lus. However, because lesions of BNST only affected behav- ioral and endocrine responses to contextual stimuli, the results do not support the notion that BNST is critical for HPA responses elicited by conditioned fear stimuli in general. Instead, the BNST may be essential specifically for contex- tual conditioned fear responses, including both behavioral and HPA responses, by virtue of its connections with the hippocampus, a structure essential to contextual condition- ing. The results are also not consistent with the hypothesis that BNST is only involved in unconditioned aspects of fear and anxiety.

Damage to the central amygdala produces differential encephalic c-fos expression in the water deprivation-partial rehydration protocol

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Central, but not basolateral, amygdala involvement in the anxiolytic-like effects of midazolam in rats in the elevated plus maze

The role of the amygdala in the mediation of fear and anxiety has been extensively investigated. However, how the amygdala functions during the organization of the anxiety-like behaviors generated in the elevated plus maze (EPM) is still under investigation. The basolateral (BLA) and the central (CeA) nuclei are the main input and output stations of the amygdala. In the present study, we ethopharmacologically analyzed the behavior of rats subjected to the EPM and the tissue content of the monoamines dopamine (DA) and serotonin (5-HT) and their metabolites in the nucleus accumbens (NAc), dorsal hippocampus (DH), and dorsal striatum (DS) of animals injected with saline or midazolam (20 and 30 nmol/0.2 mu L) into the BLA or CeA. Injections of midazolam into the CeA, but not BLA, caused clear anxiolytic-like effects in the EPM. These treatments did not cause significant changes in 5-HT or DA contents in the NAc, DH, or DS of animals tested in the EPM. The data suggest that the anxiolytic-like effects of midazolam in the EPM also appear to rely on GABA-benzodiazepine mechanisms in the CeA, but not BLA, and do not appear to depend on 5-HT and DA mechanisms prevalent in limbic structures.

Dissection of peripheral and central endogenous opioid modulation of systemic interleukin-1 beta responses using c-fos expression in the rat brain

In opiate addicts or patients receiving morphine treatment, it has been reported that the immune system is often compromised. The mechanisms responsible for the adverse effects of opioids on responses to infection are not clear but it is possible that central and/or peripheral opioid receptors may be important. We have utilised an experimental immune challenge model in rats, the systemic administration of the human pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) to study the effects of selectively blocking peripheral opioid receptors only (using naloxone methiodide) or after blocking both central and peripheral opioid receptors (using naloxone). Pre-treatment with naloxone methiodide decreased (15%) IL-1 beta-induced Fos-immunoreactivity (Fos-IR) in medial parvocellular paraventricular nucleus (mPVN) corticotropin-releasing hormone (CRH) neurons but increased responses in the ventrolateral medulla (VLM) C1 (65%) and nucleus tractus solitarius (NTS) A2 (110%) catecholamine cell groups and area postrema (136%). However no effect of blocking peripheral opioid receptors was detected in the central nucleus of the amygdala (CeA) or dorsal bed nucleus of the stria terminalis (BNST). We next determined the effect of blocking both central and peripheral opioid receptors with naloxone and, when compared to the naloxone methiodide pre-treated group, a further 60% decrease in Fos-IR mPVN CRH neurons induced by IL-1 beta was detected, which was attributed to block of central opioid receptors. Similar comparisons also detected decreases in Fos-IR neurons induced by IL-1 beta in the VLM A1, VLM C1 and NTS A2 catecholamine cell groups, area postrema, and parabrachial nucleus. In contrast, pre-treatment with naloxone increased Fos-IR neurons in CeA (98%) and dorsal BNST (72%). These results provide novel evidence that endogenous opioids can influence central neural responses to systemic IL-1 beta and also suggest that the differential patterns of activation may arise because of actions at central and/or peripheral opioid receptors that might be important in regulating behavioural, hypothalamic-pituitary-adrenal axis and sympathetic nervous system responses during an immune challenge. (c) 2005 Elsevier Ltd. All rights reserved.

Growth factor induction in intervertebral disc tissue: Observations in basic mechanisms of disc degeneration and rearrangement

The intervertebral disc is composed of concentrically arranged components: annulus fibrosus, the transition zone, and central nucleus pulposus. The major disc cell type differs in various parts of the intervertebral disc. In annulus fibrosus a spindle shaped fibroblast-like cell mainly dominates, whereas in central nucleus pulposus the more rounded chondrocyte-like disc cell is the major cell type. At birth the intervertebral disc is well vascularized, but during childhood and adolescence blood vessels become smaller and less numerous. The adult intervertebral disc is avascular and is nourished via the cartilage endplates. On the other hand, degenerated and prolapsed intervertebral discs are again vascularized, and show many changes compared to normal discs, including: nerve ingrowth, change in collagen turnover, and change in water content. Furthermore, the prolapsed intervertebral disc tissue has a tendency to decrease in size over time. Growth factors are polypeptides which regulate cell growth, extracellular matrix protease activity, and vascularization. Oncoproteins c-Fos and c-Jun heterodimerize, forming the AP-1 transcription factor which is expressed in activated cells. In this thesis the differences of growth factor expression in normal intervertebral disc, the degenerated intervertebral disc and herniated intervertebral disc were analyzed. Growth factors of particular interest were basic fibroblast growth factor (bFGF or FGF-2), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor beta (TGFβ). Cell activation was visualized by the expression of the AP-1 transcription promoters c-Fos and c-Jun. The expression was shown with either mono- or polyclonal antibodies by indirect avidin-biotin-peroxidase immunohistochemical staining method. The normal control material was collected from a tissue bank of five organ donors. The degenerated disc material was from twelve patients operated on for painful degenerative disc disease, and herniated disc tissue material was obtained from 115 patients operated on for sciatica. Normal control discs showed only TGFβ immunopositivity. All other factors studied were immunonegative in the control material. Prolapsed disc material was immunopositive for all factors studied, and this positivity was located either in the disc cells or in blood vessels. Furthermore, neovascularization was noted. Disc cell immunoreaction was shown in chondrocyte-like disc cells or in fibroblast-like disc cells, the former being expressed especially in conglomerates (clusters of disc cells). TGFβ receptor induction was prominent in prolapsed intervertebral disc tissue. In degenerated disc material, the expression of growth factors was analyzed in greater detail in various parts of the disc: nucleus pulposus, anterior annulus fibrosus and posterior annulus fibrosus. PDGF did not show any immunoreactivity, whereas all other studied growth factors were localized either in chondrocyte-like disc cells, often forming clusters, in fibroblast-like disc cells, or in small capillaries. Many of the studied degenerated discs showed tears in the posterior region of annulus fibrosus, but expression of immunopositive growth factors was detected throughout the entire disc. Furthermore, there was a difference in immunopositive cell types for different growth factors. The main conclusion of the thesis, supported by all substudies, is the occurrence of growth factors in disc cells. They may be actively participating in a network regulating disc cell growth, proliferation, extracellular matrix turnover, and neovascularization. Chondrocyte-like disc cells, in particular, expressed growth factors and oncoproteins, highlighting the importance of this cell type in the basic pathophysiologic events involved in disc degeneration and disc rearrangement. The thesis proposes a hypothesis for cellular remodelling in intervertebral disc tissue. In summary, the model presents an activation pattern of different growth factors at different intervertebral disc stages, mechanisms leading to neovascularization of the intervertebral disc in pathological conditions, and alteration of disc cell shape, especially in annulus fibrosus. Chondrocyte-like disc cells become more numerous, and these cells are capable of forming clusters, which appear to be regionally active within the disc. The alteration of the phenotype of disc cells expressing growth factors from fibroblast-like disc cells to chondrocyte-like cells in annulus fibrosus, and the numerous expression of growth factor expressing disc cells in nucleus pulposus, may be a key element both during pathological degeneration of the intervertebral disc, and during the healing process after trauma.

Expressões da espiritualidade em pessoas que vivem com HIV/Aids a partir das representações sociais acerca da síndrome: implicações para o cuidado de enfermagem

Este estudo tem como temática a espiritualidade de pessoas que vivem com HIV/Aids e como objetivo geral analisar as expressões da espiritualidade de pessoas que vivem com HIV/Aids no contexto das construções representacionais acerca da própria síndrome, com vistas à proposição de uma reflexão acerca do cuidado de enfermagem como uma tecnologia que pode estimular esta dimensão humana. Trata-se de uma pesquisa qualitativa, descritiva e exploratória, baseada nas abordagens processual e estrutural da Teoria das Representações Sociais. Quanto à metodologia, possui duas etapas: na primeira, participaram 30 pessoas com HIV/Aids em atendimento ambulatorial de um Hospital Municipal do Rio de Janeiro. Os dados foram coletados através de entrevistas semi-estruturadas e analisados através da análise de conteúdo de Bardin. Na segunda, participaram 100 pessoas atendidas no hospital supracitado. Os dados foram coletados através da técnica de evocações livres e analisados a partir do software EVOC. A partir da análise das entrevistas, emergiram cinco categorias denominadas: do sofrimento à dificuldade de encontrar sentido diante do diagnóstico; dando a volta por cima: o encontro de sentidos; da dificuldade de adesão ao tratamento à esperança de cura; os relacionamentos como forma de expressão da espiritualidade; e a presença da religiosidade no viver com HIV/Aids. Percebe-se que a descoberta diagnóstica é marcada por intenso e inevitável sofrimento, relacionado principalmente à representação social da Aids ligada à morte e à discriminação. Por outro lado, após o impacto do diagnóstico positivo, os participantes encontram um sentido para a vida, passando a ressignificá-la. A dificuldade de adesão é vista como uma vivência prejudicada da espiritualidade. Ressalta-se a esperança na cura, divina ou não-divina e há expressões de espiritualidade nos relacionamentos consigo mesmo, com o outro e com o divino. A religiosidade também se faz presente no viver com HIV/Aids principalmente para explicar a origem da Aids no mundo. Quanto à estrutura representacional da Aids, foram analisadas, comparativamente, as evocações do grupo geral, e as relacionadas ao sexo e à religião dos participantes. O possível núcleo central do grupo geral é composto pelas palavras medo, morte, tristeza e vida, elementos afetivos que também foram identificados nas entrevistas. A estrutura representacional do sexo feminino se sobrepõe a do grupo geral, diferindo-se da dos homens, que assume um caráter mais racional. Conclui-se que o sofrimento relacionado ao impacto do diagnóstico pode levar à dificuldade de encontrar sentido para a vida e, portanto, de vivenciar a espiritualidade. Ainda assim, esta dificuldade passa a ser substituída, com o tempo, por um encontro de sentido para se viver, levando a uma ressignificação da vida. A estrutura representacional permitiu a visualização de como os elementos relacionados à espiritualidade se organizam. Observa-se um processo de transformação das representações sociais da síndrome, que coincide com a presença da espiritualidade. Destaca-se o papel do enfermeiro na promoção do cuidado espiritual à pessoa com HIV/Aids.

A representação social do cuidado ao paciente soropositivo ao HIV/Aids entre profissionais de saúde

Este estudo tem como objetivo identificar a estrutura representacional do cuidado em saúde ao paciente soropositivo ao HIV/Aids entre os profissionais da equipe de saúde, descrever a representação do cuidado em saúde através das abordagens estrutural e processual, analisar o cuidado em saúde a partir das representações construídas por essa equipe e discutir a mudança de conhecimentos e práticas de cuidado em saúde a partir das representações. Pesquisa qualitativa, descritiva e exploratória, orientada pela Teoria das Representações Sociais. Os sujeitos do estudo foram profissionais de saúde atuantes em instituições públicas no Rio de Janeiro, sendo na primeira etapa, 148 profissionais de 20 instituições e, na segunda, 23 de duas instituições. A coleta de dados deu-se através de questionários de caracterização, evocações livres e entrevista semiestruturada. A análise dos dados utilizou o quadro de quatro casas a partir do software EVOC 2003, a análise de similitude e a análise lexical pelo software Alceste 4.10. Com relação à estrutura da Representação, destaca-se que o Núcleo Central foi composto por: amor, acolhimento, informação, respeito, adesão-tratamento e não-discriminação, que indicam uma dimensão relacionada aos aspectos afetivos, práticos e funcionais do cuidado. Na zona de contraste, ressalta-se a presença da proteção-profissional. A partir da análise de similitude foi possível perceber a tendência à centralidade do léxico amor. Ele organiza a representação e possui forte ligação com o termo solidariedade. Na análise realizada pelo Alceste, foram definidas seis classes: A constituição da equipe de saúde e o processo de cuidar: definições, práticas e dificuldades; As práticas de proteção adotadas pelos profissionais frente ao HIV; As formas de enfrentamento diante do diagnóstico positivo ao HIV; Atitudes profissionais: avaliações e julgamentos; As memórias sociais sobre a aids: origem, circulação, informação e imagens e, por fim, A epidemia de aids nos dias atuais. Conclui-se que a representação social do cuidado entre profissionais de saúde tem, em sua estrutura e organização, a interação sustentada por uma arqueologia que se liga aos considerados sentimentos nobres e às ações de abnegação e de superação humanas, tendo como elemento central o amor que caracteriza suas ações e influencia sua práxis. A importância da oferta desse cuidado amoroso está em sua relação com a humanização das ações assistenciais, atendendo à demanda do indivíduo durante a manifestação da doença, respeitando sua singularidade como ser humano e facilitando seu processo de adoecimento e busca pela melhoria da saúde.

As relações estabelecidas entre a terapia Reiki e o bem estar subjetivo mediadas pelas representações sociais

O objetivo do presente estudo é analisar o impacto da terapia Reiki no bem estar subjetivo e suas representações sociais em uma universidade pública do Rio de Janeiro. Trata-se de uma pesquisa quanti-qualitativa, com abordagem experimental, apoiado na Teoria de Representações Sociais. O grupo estudado foi composto de 60 sujeitos que não tiverem acesso à terapia anteriormente entrevistados antes e depois de três sessões de Reiki. Os dados foram coletados através de quatro instrumentos: questionário de identificação dos sujeitos, questionário de representação social do Reiki, questionário de evocação livre e escala de Bem estar Subjetivo. A análise dos dados foi realizada com estatística descritiva e inferencial com o software SPSS 19, análise estrutural e análise de conteúdo das representações sociais, a partir do software EVOC. Os sujeitos participantes são do sexo feminino (88,33%); nível superior (76,66%); discentes de ensino superior e médio e enfermeiros (48,34%); está empregado (56,67%); renda pessoal inferior a R$ 1.000,00 (41,67%); solteiro (61,67%); vive sozinho (68,33%); tem companheiro fixo (68,33%); sem doença (58,33%); uso de terapia não convencional (63,33%); tem religião (88,33%) e religião católica (33,33%) e evangélica (21,67%). Quanto às representações sociais, a busca do Reiki antes e depois do experimento revelou duas categorias com maior frequência, que são: equilíbrio da saúde mental, antes (35,44%) e depois (50,65%) e equilíbrio da saúde física, antes (16,46%) e depois (27,27%). Quanto à estrutura representacional do Reiki, o possível núcleo central dos dois grupos analisados foi composto pelas palavras energia, relaxamento e tranquilidade, configurando-se como uma dimensão funcional e positiva do Reiki e não apresentando variação da representação antes e depois da realização da terapia. O estudo experimental apresentou como resultados: No experimento I: diferença estatisticamente significante na dimensão afeto positivo, com escore maior no grupo de sujeitos que recebeu a terapia Reiki comparado aos que não receberam. No experimento II: diferença estatisticamente significante na dimensão afeto negativo, com escore maior no grupo de sujeitos que recebeu informação do Reiki associado à religiosidade comparado àqueles que receberam outros tipos de informação. E no experimento III: na dimensão afeto positivo, observou-se que todos os escores se elevaram, apontando para um efeito generalizado e inespecífico da realização do Reiki e da informação sobre o afeto positivo, exceto no que se refere à informação de espiritualidade que apresentou inversão das médias. No afeto negativo observou-se que todos os escores diminuíram, apontando para um efeito generalizado e inespecífico da realização do Reiki.Na dimensão cognitiva as médias dos escores antes e depois das manipulações experimentais praticamente não se alteraram. Conclui-se que a terapia Reiki favoreceu na manutenção do equilíbrio energético dos usuários, através de relaxamento, tranquilidade e sentimentos positivos, proporcionando, assim, efeitos psicológicos saudáveis, nutrindo e fortificando o campo energético dos usuários que participaram do estudo.