Alterações na evocação de uma memória aversiva ao liongo do ciclo estral de ratas: influências da transmissão gabaérgica na amígdala

GABAergic neurotransmission has been implicated in many aspects of learning and memory, as well as mood and anxiety disorders. The amygdala has been one of the major focuses in this area, given its essential role in modulating emotionally relevant memories. However, studies with male subjects are still predominant in the field. Here we investigated the consequences for an aversive memory of enhancing or decreasing GABAergic transmission in the basolateral nucleus of the amygdala (BLA). Wistar female rats were trained in the plus-maze discriminative avoidance task, in which they had to learn to avoid one of the enclosed arms where an aversive stimulus consisting of a bright light and a loud noise was given (day 1). Fifteen minutes before the test session (day 2) animals received 0,2 μL infusions of either saline solution, the GABAergic agonist muscimol (0,05 mg/ml), or the GABAergic antagonist bicuculine (0,025 mg/ml) bilaterally intra-BLA. On the test day, females in proestrous or estrous presented adequate retrieval and did not extinguish the task, while females in metestrous or diestrous presented impaired retrieval. In the first group, muscimol infusion impaired retrieval and bicuculline had no effect, suggesting naturally low levels of GABAergic transmission in the BLA of proestrous and estrous females. In the second group, muscimol infusion had no effect and bicuculline reversed retrieval impairment, suggesting naturally high levels of GABAergic transmission in the BLA of metestrous and diestous females. Additionally, proestrous and estrous females presented higher anxiety levels compared to metestrous and diestrous females, which could explain better performance of this group. On the other hand, BLA GABAergic system did not interfere with the innate fear response because drug infusions had no effect in anxiety. Thus, retrieval alterations caused by the GABAergic drugs were probably related specifically to memory processes

Mulheres com lúpus eritematoso sistêmico: sintomas depressivos e apoio social percebido

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease, rare, multisystem, with a very heterogeneous clinical and serological manifestations standard. The patient, in addition to suffering injuries on his physical and physiological functioning, may also face a number of psychosocial problems. Research indicates that SLE can cause significant damage to the psychological realm, especially with the presence of anxiety and depression. In 1999, the American College of Rheumatology (ACR), proposed the establishment of 19 neuropsychiatric clinical syndromes attributed to SLE. Depression lies between mood disorders and is one of the most common psychiatric manifestations in this group, being found more frequently in these patients than in the general population. Studies also suggest that social support plays an important role in the development of coping strategies, in SLE management and depression. This study has as main objective verify the association between depressive symptoms and perceived social support in patients with SLE. The specific objectives turned to: investigte the prevalence of depressive symptoms; investigate the perceived social support and verify if there is an association between depression, social support and sociodemographic variables. We used a sociodemographic questionnaire, the Beck Depression Scale, and the Perceived Social Support Scale. The analysis was performed through descriptive and inferential statistics. The final sample could count with 79 SLE women, with an average age of 35.7 years. 44 (55.7%) of the participants were married. Only 6 (7.59%) had completed higher education and 32 (40.51%) have not finished high school. Seventy-one (89.87%) had an income below three minimum salaries and 71 (89.87) practiced a religion, and the Catholic (67.71%) was the most mentioned by them. Of the total sample, 37 (46.74%) had been diagnosed SLE more than 7 years before, and 25 (31.65%) had the disease for more than 10 years. Only 19 (24.05%) had some work activity. Forty-two of them (53.17%) had depressive symptoms levels from mild to severe, and 51 (64.46%) reported pain levels of 5, or above. The study found a significant association between depressive symptoms and pain (p = 0.013) and depressive symptoms and work activity (p = 0.02). When we examined the perception of social support, the results showed high levels among participants. Using the Spearman correlation test we found a strong correlation between depressive symptoms and social support (p= 0,000037). It means that the higher the frequency of support, the lower the score of depression. These findings are relevant because depressive symptoms in patients with SLE have a multicausal and multifactorial character and may remain unnoticed, since many of them are confused with the manifestations of the disease. This fact requires a careful assessment from professionals, not only in the clinical setting, but also considering other psychosocial reasons, that may be influencing the emergence or worsening of symptoms. These results also corroborate other studies, which not only confirm the predictive role of social support in the physical wellbeing, but also in the psychological.

Mulheres com lúpus eritematoso sistêmico: sintomas depressivos e apoio social percebido

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease, rare, multisystem, with a very heterogeneous clinical and serological manifestations standard. The patient, in addition to suffering injuries on his physical and physiological functioning, may also face a number of psychosocial problems. Research indicates that SLE can cause significant damage to the psychological realm, especially with the presence of anxiety and depression. In 1999, the American College of Rheumatology (ACR), proposed the establishment of 19 neuropsychiatric clinical syndromes attributed to SLE. Depression lies between mood disorders and is one of the most common psychiatric manifestations in this group, being found more frequently in these patients than in the general population. Studies also suggest that social support plays an important role in the development of coping strategies, in SLE management and depression. This study has as main objective verify the association between depressive symptoms and perceived social support in patients with SLE. The specific objectives turned to: investigte the prevalence of depressive symptoms; investigate the perceived social support and verify if there is an association between depression, social support and sociodemographic variables. We used a sociodemographic questionnaire, the Beck Depression Scale, and the Perceived Social Support Scale. The analysis was performed through descriptive and inferential statistics. The final sample could count with 79 SLE women, with an average age of 35.7 years. 44 (55.7%) of the participants were married. Only 6 (7.59%) had completed higher education and 32 (40.51%) have not finished high school. Seventy-one (89.87%) had an income below three minimum salaries and 71 (89.87) practiced a religion, and the Catholic (67.71%) was the most mentioned by them. Of the total sample, 37 (46.74%) had been diagnosed SLE more than 7 years before, and 25 (31.65%) had the disease for more than 10 years. Only 19 (24.05%) had some work activity. Forty-two of them (53.17%) had depressive symptoms levels from mild to severe, and 51 (64.46%) reported pain levels of 5, or above. The study found a significant association between depressive symptoms and pain (p = 0.013) and depressive symptoms and work activity (p = 0.02). When we examined the perception of social support, the results showed high levels among participants. Using the Spearman correlation test we found a strong correlation between depressive symptoms and social support (p= 0,000037). It means that the higher the frequency of support, the lower the score of depression. These findings are relevant because depressive symptoms in patients with SLE have a multicausal and multifactorial character and may remain unnoticed, since many of them are confused with the manifestations of the disease. This fact requires a careful assessment from professionals, not only in the clinical setting, but also considering other psychosocial reasons, that may be influencing the emergence or worsening of symptoms. These results also corroborate other studies, which not only confirm the predictive role of social support in the physical wellbeing, but also in the psychological.

Avaliação comportamental e neuroquímica de ratos em dessincronização forçada: possíveis implicações para um modelo animal de oscilações no humor

Bipolar disorder has been growing in several countries. It is a disease with high mortality and has been responsible by the social isolation of the patients. Bipolar patients have alterations in circadian timing system, showing a phase shift in various physiological variables. There are several arguments demonstrating alterations in circadian rhythms may be part of the bipolar disorder pathophysiology. Given the necessity for further elucidation, the goal of this study was to validate the forced desynchronization protocol as an animal model for bipolar disorder. To do this, Wistar rats were submitted to a forced desynchronization protocol which consists in a symmetrical light dark cycle with 22h. Under this protocol, rats dissociate the locomotor activity rhythm into two components: one synchronized to the light / dark cycle with 22h, and another component with period longer than 24 hours following the animal endogenous period. These rhythms with different periods sometimes there is coincidence, which we named CAP (Coincidence Active Phase) and the opposite phase, non-coincidence, called NCAP (Non-Concidence Active Phase). The hypothesis is that in CAP animals present a mania-like behavior and animals in NCAP depressive-like behavior. We found some evidence described in detail throughout this thesis. In sum, the animals under forced desynchronization protocol were more stressed, showed an increase in stereotypic behaviors such as grooming and reduction in other behaviors such as risk assessment and vertical exploration when compared to the control group. The CAP animals showed increased locomotor activity, especially during the dark phase when compared to controls (rats under T24) and less depressive behavior in the forced swim test. The animals in NCAP showed a higher anxiety in elevated plus maze, but they don t have ahnedonia. The animals under dissociation have more labeled 5HT1A cells at the amygdala area, which appoint that they have more amygdala inhibition. Taking these data together, we could partially validated the forced desynchronization protocol as an animal model for mood oscillations

Humor gráfico: o sorriso pensante e a formação do leitor

This research investigates the graphic humor, in particular the political cartoon and the cartoon, texts characterized by mixing visual-oral language, and its contribution in the formation of the reader. Recovers the main theories about the comicality in general and verifies the presence of these concepts into the texts of graphic humor and how they articulate themselves within the process of seducing the reader. Grounded in the studies of Umberto Eco about the cultural industry products and its relations with the literary theories and the aesthetics reception. After analysing texts of graphic humor, the study concludes that the triad, image-word-humor reveal a sophisticated arrangement which allows the reader to practice effectively the political cartoons and cartoons of production, of sense, cooperating in such a singular manner to the formation of a reflexive reader

Atenção à saúde mental na Estratégia Saúde da Família no Município de Parnamirim/RN: opinião dos profissionais, dos portadores de transtornos mentais e seus acompanhantes

This study aims to analyze and compare the opinion of professionals, managers and users about the mental health care in the Family Health Strategy (FHS). It is characterized as an Operations Research or Health System Research with a cross-sectional design and a descriptive quantitative nature. The study was developed from the application of the Opinion Measurement Scale allied to techniques of observation and structured interview in the city of Parnamirim / RN. The sample consists of 409 subjects, 209 professionals of the Family Health Strategy, 30 of the Oral Health Strategy, 19 of the Family Health Support Center, 24 directors of Basic Health Units, plus 68 users with mental disorders and 59 caregivers, respecting the ethical parameters of Resolution 196/96 of the National Health Council, trial registration number: CAAE 0003.0.051.000-11. Quantitative data were submitted to the Epi-info 3.5.2 for analysis. The network of mental health in Parnamirim involves the flow between the FHS, Psychosocial Care Centers, clinics and hospitals, having as main barriers the fragility of the referral and counter-referral system, of the municipal health conferences, of the FHS teams by the limitations in material and human resources as well as the population´s lack of acknowledge about the organization of the mental health network, issues that affect the integral attention. Even though the FHS professionals recognize the importance of their actions, they question their role in mental health care, experiencing difficulties in accessing psychiatric services (76.5%). Although most agree that the mentally ill is best treated in the family than in hospital (65.2%), the community health workers were the predominant category in the partial or total disagreement of this statement (40.8%), who is the professional in greater contact with the family. Nevertheless the caregivers miss the support of the FHS as the main focus of attention is on revenue control. The views of professionals, mental patients and caregivers converged in several statements, showing the main weaknesses to be focused by the mental health network of the city, as the perceptions that: (a) physical strength is needed to take care of mental patients for its tendency to aggression, requiring it to stay in the sanatorium for representing danger to society, (b) only a psychiatrist can help the person with emotional problems, (c) the user of alcohol and drugs does not necessarily develop mental illness, (d) the access barriers and doubts about the quality of psychiatric services, (e) caring of a mental health patient does not bring suffering to professionals. Therefore, the commitment to consensus building, monitoring and evaluation of the network are important mechanisms for an effective management system, reflecting in the importance of strengthening the health conferences and approximating different institutions. The results reinforce the importance of strengthening primary care through programs of continuing education focusing on the actions and functions of professionals in accordance with its competences and duties what contribute to the organization and response of mental health care, favoring user´s care and the promotion of family health

Cartografias do desejo em asfalto selvagem - engraçadinha, seus amores e seus pecados: humor, erotismo e o pornógrafo no romance rodrigueano

Trata-se nesta dissertação de estabelecer, partindo do pensamento contemporâneo francês da linha deleuziana e guattariana, sobretudo, uma analítica do desejo capaz de reconfigurar o romance de Nelson Rodrigues, Asfalto selvagem: Engraçadinha, seus amores e seus pecados, desterritorializá-lo em relação à tradição crítica e estética, fundada no paradigma realista-naturalista enraizado no pensamento literário brasileiro, especificamente no século XX. Movemo-nos por discussões sobre o autor e sobre o romance, empreendidas por Rolnik, interlocutora de Guattari, o qual está ligado aos novos paradigmas estéticos, à questão da produção de subjetividades, à micropolítica, às multiplicidades e às minorias. Buscamos contribuir para esse redimensionamento, colocando-nos na perspectiva cartográfica e rizomática para surpreender, em Asfalto, seus processos de subjetivação, incidindo sobre as singularidades selvagens, considerando os conceitos de Foucault, aplicados à construção literária enquanto espaço heterotópico, configurando a experiência do fora, como princípios estéticos. Veremos que as personagens, com foco em Engraçadinha, funcionam, como pequenas máquinas desejantes, Corpos sem Órgãos, moléculas desestabilizando as formações molares. Destarte, Nelson Rodrigues, na perspectiva da produção autoral, torna-se o pornógrafo, o literato iterador, como agenciador de uma palavra perversa, para além dos dogmas, da cena romantizada, originando, em sua poética, a revelação da obs-cena, a obscenidade, como crítica às instituições falidas. Trazemos, nesse sentido, referências de Bataille, quanto ao que na atividade estética se relaciona com o excedente da visão, relacionados ao espaço tático-ótico, concepção deleuziana referentes ao corpo-linguagem, pornografia, pornógrafo, narrativas abomináveis. Acompanhamo-nos, pois, dos conceitos da problemática da diferença e da alteridade, repercutindo na larvaridade, nas afecções, que abrem vias comunicantes com fenômenos extremos, atuantes em torno do mesmo e do outro, trazendo a rizomaticidade do mal e da monstruosidade para a construção estética de Asfalto selvagem, vistos sob a ótica de Bataille, Deleuze, Baudrillard, em ensaios que rompem o olhar estrutural em torno da obra e oferecem subsídios para a construção de uma cartografia outra, o território do ficcional, habitado por um povo por vir, na perspectiva tratada por Deleuze e por Blanchot

Entre Millôr e Derrida: o humor enquanto experiência da alteridade e do impossível

Brazilian humorist Millôr Fernandes has a widespread work, from literature to visual arts and journalism. Yet there is the indelible mark of humor, wherever it is. In this dissertation, I propose a reading of his work by deploying French philosopher Jacques Derrida, emphasizing how the construction of the other happens. I aim at Millôr Definitivo: A Bíblia do Caos, but other works will be contemplated when necessary. In order to carry out the analysis, I will offer a general exposition of Millorian work (especially Millôr Definitivo:A Bíblia do Caos) and a general sketch of Derridian philosophy, centered on his discussion on Western philosophy, literature and alterity. At the analysis itself, I will set the methodological axis on the quasi-concept of invention. The analysis shall stress the hypothesis of humor as the experience of alterity and impossible, showing off the humorist as the totally other. In the Millorian text, that experience is characterized by conflictivity, without possibility of resolution

Experiência, memória e humor: representações sociais em as filhas do arco-íris e em primeiras estórias.

Este trabalho analisa relações da experiência, memória e humor e investiga representações da infância, da velhice, da loucura e do alcoolismo no romance As Filhas do Arco-Íris, de Eulício Farias de Lacerda e em contos de Primeiras Estórias, de Guimarães Rosa, destacando-se que meninos, velhos, cegos e loucos, mesmo marginalizados, podem ser encarados como atores sociais na formação das comunidades. Verifica-se que essas personagens constituem uma coletividade no sentido de evocar a representação de indivíduos. Também se procura examinar práticas literárias e culturais no âmbito do sistema literário brasileiro, com ênfase em regionalismos, oralidade e considerações sobre literatura e sociedade. É desse modo que se busca observar que as obras destacadas estão inseridas numa discussão moderna acerca do desenvolvimento sociocultural. Portanto, a preocupação desta pesquisa deriva da discussão moderna acerca do desenvolvimento social. Diante disso, observa-se nos textos de Guimarães Rosa e de Eulício Farias um tratamento narrativo em torno dessas personagens, enfatizando que as situações vividas por eles envolvem experiências que os levam a construir, em relação ao contexto social, aspectos de amadurecimento, rememoração, compartilhamento, encantamento, viagem ao desconhecido, movimentos históricos, alegrias e tristezas, sempre demonstrando uma sintonia com a temática da modernidade. Assim, as condições sociais são interpretadas para evidenciar e confrontar: discriminação, amizade, conflito, respeito, marginalização, memória social. Ainda são estabelecidas comparações entre personagens do romance As Filhas do Arco-Íris com as de alguns contos de Primeiras Estórias, salientando-se considerações sobre o narrador, as inter-relações, regionalismo e relações entre literatura, organização e processo social. Esta pesquisa tem por base o conceito de sistema literário consolidado idealizado por Antonio Candido e os postulados de estudiosos e teóricos como: Walter Benjamin, Jacqueline Held, Mikhail Bakhtin, Roland Barthes, Ana Paula Pacheco, Serge Moscovici, François Laplantine, Liane Trindade

Análise de grafos aplicada a relatos de sonhos: ferramenta diagnóstica objetiva e diferencial para psicose esquizofrênica e bipolar

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Administração repetida de baixas doses de reserpina: um possível modelo para o estudo de déficits cognitivos e motores associados à Doença de Parkinson

Parkinson's disease (PD) is one of the most common neurodegenerative brain disorders and is characterized primarily by a progressive degeneration of dopaminergic neurons nigroestriatais. The main symptoms of this disease are motor alterations (bradykinesia, rigidity, tremor at rest), which can be highly disabling in advanced stages of the condition. However, there are symptomatic manifestations other than motor impairment, such as changes in cognition, mood and sensory systems. Animal models that attempt to mimic clinical features of PD have been used to understand the behavioral and neural mechanisms underlying neurophysiological disturbance of this disease. However, most models promote an intense and immediate motor impairment, consistent with advanced stages of the disease, invalidating these studies for the evaluation of its progressive nature. The administration of reserpine (a monoamine depletor) in rodents has been considered an animal model for studying PD. Recently we found that reserpine (in doses lower than those usually employed to produce the motor symptoms) promotes a memory deficit in an aversive discrimination task, without changing the motor activity. It was suggested that the administration of this drug in low doses can be useful for the study of memory deficits found in PD. Corroborating this data, in another study, acute subcutaneous administration of reserpine, while preserving motor function, led to changes in emotional context-related (but not neutral) memory tasks. The goal of this research was to study the cognitive and motor deficits in rats repeatedly treated with low doses of reserpine, as a possible model that simulates the progressive nature of the PD. For this purpose, 5-month-old male Wistar rats were submitted to a repeated treatment with vehicle or different doses of reserpine on alternate days. Cognitive and motor parameters and possible changes in neuronal function were evaluated during treatment. The main findings were: repeated administration of 0.1 mg / kg of reserpine in rats is able to induce the gradual appearance of motor signs compatible with progressive features found in patients with PD; an increase in striatal levels of oxidative stress and changes in the concentrations of glutamate in the striatum were observed five days after the end of treatment; in animals repeatedly-treated with 0. 1 mg/kg, cognitive deficits were observed only after the onset of motor symptoms, but not prior to the onset of these symptoms; 0.2 mg / kg reserpine repeated treatment has jeopardized the cognitive assessment due to the presence of severe motor deficits. Thus, we suggest that the protocol of treatment with reserpine used in this work is a viable alternative for studies of the progressive appearance of parkinsonian signs in rats, especially concerning motor symptoms. As for the cognitive symptoms, we suggest that more studies are needed, possibly using other behavioral models, and / or changing the treatment regimen

Indicadores de transtornos de estresse pós-traumático em bombeiros militares

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Estratégias de cuidados por familiares de portadores de transtornos mentais severos residentes na zona rural do alto sertão paraibano

In the current configuration of the Brazilian Psychiatric Reform, family plays a key role in mental health care: shared responsibility and active participation in the process of rehabilitation of people with severe mental disorders. It´s considered that the family member who cares can help users in their daily tasks and articulating trajectories, networks and ways to potentiate social connections. This research was motivaded by interest in the subject and by the lack of research and studies about this reality in rural areas. This study aimed to identify ways of mental health care by relatives of severe mental disorder patients living in rural zone located at sertão of Paraiba. Methodologically was made a work with qualitative research structured in two moments. In the first one, was held a Documentary Research in CAPS II in order to identify: a) users living in rural that had a history of at least one psychiatric hospitalization, b) users who no longer use the reference service (CAPS II) for at least one year. The second stage consisted by home visits and semi-structured interviews with eleven families in rural areas. Results pointed out a profile composed by 56 users: 56 women and 26 men aged between 50 and 64 years, unmarried, without study, farmers and housewives, living six miles from CAPS II and carriers with severe mental disorders. Strategies and resources used by the families for mental health care were: religion, work, medication and help from relatives, neighbors and community. Factors related to non-use of substitute services were lack of internment in CAPS II and lack of money and transportation. The hospital, the house arrest, the police aid and religion were strategies used by family members as support to psychiatric crises. The data pointed to non-solving of care offered by psychosocial support network and the importance of redirecting practices aligned to the asylum model in favor of psychosocial strategies that aimed at rehabilitation and community participation in mental health care

Efeitos in vivo e in vitro de agonistas parciais do receptor NOP: implicações para o tratamento da ansiedade, depressão e mania

Introduction: This study aimed to investigate the effects of the two peptide NOP partial agonists (UFP-113 and [F/G]N/OFQ(1-13)NH2) and the non peptide NOP partial agonist (AT-090) in the mouse emotional behavior as well as in the intracellular transduction pathways following the receptor binding. Methods: Male Swiss or CD-1 mice were used in this study together with NOP(+/+) and NOP(-/-) mice. The elevated plus maze (EPM) was used to evaluate the effects of compounds on anxiety-like behaviors. Diazepam and the NOP agonists, N/OFQ and Ro 65-6570, were used as positive controls in the EPM. NOP(+/+) and NOP(-/-) mice were used to evaluate the selectivity of those compounds that induced anxiolytic-like behaviors. The forced swim test (FST) was used to evaluate the effects of compounds on depressive-like behaviors. Nortriptyline and the NOP antagonists, UFP-101 and SB-612111, were used as positive controls in the FST. The effects of N/OFQ, UFP-101, SB-612111, UFP-113, [F/G]N/OFQ(1-13)NH2, and AT-090 were assessed in the methylphenidate-induced hyperlocomotion (MIH) test; in this assay valproate was used as positive control. The G protein and β-arrestin 2 transduction pathways of NOP receptor agonists (N/OFQ and Ro 65-6570), antagonist (UFP-101), and partial agonists (UFP-113, [F/G]N/OFQ(1-13)NH2, and AT-090) were also evaluated using an innovative assay that measures a bioluminescence resonance energy transfer process. For this, cell lines permanently co-expressing the NOP receptor coupled to luciferase (energy donor), and green fluorescent protein (energy acceptor) coupled to one of the effector proteins (G protein or β-arrestin 2) were used. Results: Diazepam (1 mg/kg), N/OFQ (1 nmol), Ro 65-6570 (0.1 mg/kg), and AT-090 (0.01 mg/kg) induced anxiolytic-like effect in mice in the EPM. The effects of Ro 65-6570 and AT-090 were selective to NOP receptor. UFP-113 (0.01-1 nmol) and [F/G]N/OFQ(1-13)NH2 (0.1-3 nmol) were inactive in the EPM. In the FST, nortriptyline (30 mg/kg), UFP-101 (10 nmol), SB-612111 (10 mg/kg), UFP-113 (0.01 and 0.1 nmol), and [F/G]N/OFQ(1-13)NH2 (0.3 and 1 nmol) induced antidepressant-like effects, while AT-090 (0.001-0.1 mg/kg) was inactive in this assay. The effects of UFP-113 and [F/G]N/OFQ(1-13)NH2 were selective to NOP receptor. Valproate (400 mg/kg) counteracted methylphenidate (MPH, 10 mg/kg)-induced hyperlocomotion in mice in the open field. N/OFQ (1 nmol), UFP-113 (0.01-0.1 nmol), and [F/G]N/OFQ(1-13)NH2 (1 nmol) were also able to reduce the MPH-induced hyperlocomotion, without changing the locomotor activity per se. The effect of UFP-113 was selective to NOP receptor. The UFP-101 (10 nmol), SB-612111 (10 mg/kg), and AT-090 (0.001-0.03 mg/kg) did not change the hyperlocomotor effect of methylphenidate. In vitro, N/OFQ and Ro 65-6570 behaved as NOP full agonists for G-protein and β-arrestin 2 pathways. AT-090 behaved as NOP receptor partial agonist for both transduction pathways, while UFP-113 and [F/G]N/OFQ(1-13)NH2 behaved as partial agonists and antagonists of NOP receptor for NOP/G protein and NOP/β-arrestin 2, respectively. UFP-101 behaved as NOP receptor antagonist for both transduction pathways. Conclusion: NOP ligands producing same effects on NOP/G protein interaction (partial agonism), but with opposite effects on β-arrestin 2 recruitment (partial agonism vs antagonism), can promote different in vivo effects on anxiety and mood as it was observed in the behavioral tests. This work corroborates the potential of NOP receptor as an innovative pharmacological target for the treatment of emotional disorders.

Efeitos in vivo e in vitro de agonistas parciais do receptor NOP: implicações para o tratamento da ansiedade, depressão e mania

Introduction: This study aimed to investigate the effects of the two peptide NOP partial agonists (UFP-113 and [F/G]N/OFQ(1-13)NH2) and the non peptide NOP partial agonist (AT-090) in the mouse emotional behavior as well as in the intracellular transduction pathways following the receptor binding. Methods: Male Swiss or CD-1 mice were used in this study together with NOP(+/+) and NOP(-/-) mice. The elevated plus maze (EPM) was used to evaluate the effects of compounds on anxiety-like behaviors. Diazepam and the NOP agonists, N/OFQ and Ro 65-6570, were used as positive controls in the EPM. NOP(+/+) and NOP(-/-) mice were used to evaluate the selectivity of those compounds that induced anxiolytic-like behaviors. The forced swim test (FST) was used to evaluate the effects of compounds on depressive-like behaviors. Nortriptyline and the NOP antagonists, UFP-101 and SB-612111, were used as positive controls in the FST. The effects of N/OFQ, UFP-101, SB-612111, UFP-113, [F/G]N/OFQ(1-13)NH2, and AT-090 were assessed in the methylphenidate-induced hyperlocomotion (MIH) test; in this assay valproate was used as positive control. The G protein and β-arrestin 2 transduction pathways of NOP receptor agonists (N/OFQ and Ro 65-6570), antagonist (UFP-101), and partial agonists (UFP-113, [F/G]N/OFQ(1-13)NH2, and AT-090) were also evaluated using an innovative assay that measures a bioluminescence resonance energy transfer process. For this, cell lines permanently co-expressing the NOP receptor coupled to luciferase (energy donor), and green fluorescent protein (energy acceptor) coupled to one of the effector proteins (G protein or β-arrestin 2) were used. Results: Diazepam (1 mg/kg), N/OFQ (1 nmol), Ro 65-6570 (0.1 mg/kg), and AT-090 (0.01 mg/kg) induced anxiolytic-like effect in mice in the EPM. The effects of Ro 65-6570 and AT-090 were selective to NOP receptor. UFP-113 (0.01-1 nmol) and [F/G]N/OFQ(1-13)NH2 (0.1-3 nmol) were inactive in the EPM. In the FST, nortriptyline (30 mg/kg), UFP-101 (10 nmol), SB-612111 (10 mg/kg), UFP-113 (0.01 and 0.1 nmol), and [F/G]N/OFQ(1-13)NH2 (0.3 and 1 nmol) induced antidepressant-like effects, while AT-090 (0.001-0.1 mg/kg) was inactive in this assay. The effects of UFP-113 and [F/G]N/OFQ(1-13)NH2 were selective to NOP receptor. Valproate (400 mg/kg) counteracted methylphenidate (MPH, 10 mg/kg)-induced hyperlocomotion in mice in the open field. N/OFQ (1 nmol), UFP-113 (0.01-0.1 nmol), and [F/G]N/OFQ(1-13)NH2 (1 nmol) were also able to reduce the MPH-induced hyperlocomotion, without changing the locomotor activity per se. The effect of UFP-113 was selective to NOP receptor. The UFP-101 (10 nmol), SB-612111 (10 mg/kg), and AT-090 (0.001-0.03 mg/kg) did not change the hyperlocomotor effect of methylphenidate. In vitro, N/OFQ and Ro 65-6570 behaved as NOP full agonists for G-protein and β-arrestin 2 pathways. AT-090 behaved as NOP receptor partial agonist for both transduction pathways, while UFP-113 and [F/G]N/OFQ(1-13)NH2 behaved as partial agonists and antagonists of NOP receptor for NOP/G protein and NOP/β-arrestin 2, respectively. UFP-101 behaved as NOP receptor antagonist for both transduction pathways. Conclusion: NOP ligands producing same effects on NOP/G protein interaction (partial agonism), but with opposite effects on β-arrestin 2 recruitment (partial agonism vs antagonism), can promote different in vivo effects on anxiety and mood as it was observed in the behavioral tests. This work corroborates the potential of NOP receptor as an innovative pharmacological target for the treatment of emotional disorders.