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1.
Adv Exp Med Biol ; 1191: 103-120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002925

RESUMO

Oxytocin, a neuropeptide synthesized by the hypothalamus, plays a central role in human social behavior, social cognition, anxiety, mood, stress modulation, and fear learning and extinction. The relationships between oxytocin and psychiatric disorders including depression, anxiety, schizophrenia, and autism spectrum disorder have been extensively studied. In this chapter, we focus on the current knowledge about oxytocin and anxiety disorder. We discuss the anxiolytic effects of oxytocin in preclinical and clinical findings, possible related neurobehavioral mechanisms (social cognition, fear learning, and extinction), related neurotransmitter and neuroendocrine systems (hypothalamus-pituitary-adrenal axis, serotoninergic, and GABAergic systems), and studies regarding plasma levels of oxytocin, genetic and epigenetic findings, and effects of intranasal oxytocin in DSM-5 anxiety disorder (primarily social anxiety disorder and separation anxiety disorder) patients.


Assuntos
Transtornos de Ansiedade/metabolismo , Ocitocina/metabolismo , Ansiedade/metabolismo , Medo , Humanos , Comportamento Social
2.
Adv Exp Med Biol ; 1191: 121-140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002926

RESUMO

Discovery of innovative anxiolytics is severely hampering. Existing anxiolytics are developed decades ago and are still the therapeutics of choice. Moreover, lack of new drug targets forecasts a severe jeopardy in the future treatment of the huge population of CNS-diseased patients. We simply lack the knowledge on what is wrong in brains of anxious people (normal and diseased). Translational research, based on interacting clinical and preclinical research, is extremely urgent. In this endeavor, genetic and genomic approaches are part of the spectrum of contributing factors. We focus on three druggable targets: serotonin transporter, 5-HT1A, and GABAA receptors. It is still uncertain whether and how these targets are involved in normal and diseased anxiety processes. For serotonergic anxiolytics, the slow onset of action points to indirect effects leading to plasticity changes in brain systems leading to reduced anxiety. For GABAA benzodiazepine drugs, acute anxiolytic effects are found indicating primary mechanisms directly influencing anxiety processes. Close translational collaboration between fundamental academic and discovery research will lead to badly needed breakthroughs in the search for new anxiolytics.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/fisiopatologia , Ansiedade/fisiopatologia , Descoberta de Drogas , Neurotransmissores/metabolismo , Pesquisa Médica Translacional , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Humanos
3.
Adv Exp Med Biol ; 1191: 155-167, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002928

RESUMO

Anxiety disorders are a complex set of illnesses in which genetic factors, particularly stress, play a role in the etiopathogenesis. In recent years, inflammation and intestinal microbiota have also been included in this complex network of relationships. The functions associated with tryptophan catabolism and serotonin biosynthesis have long been associated with anxiety disorders. Tryptophan catabolism progresses toward the path of the kynurenine in the presence of stress and inflammation. The catabolism of kynurenine is a pathway in which many enzymes play a role and a large number of catabolites with neuroactive properties occur. The body's serotonin biosynthesis is primarily performed by enterochromaffin cells located in the intestines. A change in the intestinal microbiota composition (dysbiosis) directly affects the serotonin biosynthesis. Stress, unhealthy nutrition, and the use of antibiotics cause dysbiosis. In the light of this new perspective, the role of dysbiosis-induced inflammation and kynurenine pathway catabolites activated sequentially come into prominence in the etiopathogenesis of anxiety disorders.


Assuntos
Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Microbioma Gastrointestinal , Cinurenina/metabolismo , Disbiose/metabolismo , Disbiose/microbiologia , Humanos , Serotonina/biossíntese , Serotonina/metabolismo
4.
Adv Exp Med Biol ; 1191: 523-541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002944

RESUMO

Exposure therapy, a key treatment for anxiety disorders, can be modelled in the laboratory using Pavlovian fear extinction. Understanding the hormonal and neurobiological mechanisms underlying fear extinction in females, who are twice more likely than males to present with anxiety disorders, may aid in optimising exposure therapy outcomes in this population. This chapter will begin by discussing the role of the sex hormones, estradiol and progesterone, in fear extinction in females. We will also propose potential mechanisms by which these hormones may modulate fear extinction. The second half of this chapter will discuss the long-term hormonal, neurological and behavioural changes that arise from pregnancy and motherhood and how these changes may alter the features of fear extinction in females. Finally, we will discuss implications of this research for the treatment of anxiety disorders in women with and without prior reproductive experience.


Assuntos
Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/terapia , Ansiedade/metabolismo , Ansiedade/terapia , Estradiol/metabolismo , Progesterona/metabolismo , Reprodução , Ansiedade/psicologia , Transtornos de Ansiedade/psicologia , Extinção Psicológica , Medo , Feminino , Humanos , Gravidez
5.
Med Sci Monit ; 25: 7889-7897, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31634896

RESUMO

BACKGROUND Empathy between doctor and patient has an important bearing on patient health. The purpose of this study was to assess whether anxiety, sleep quality, and self-efficacy of patients have mediating effects in the relationship of patient-reported physician empathy and inflammatory factor in ulcerative colitis (UC) patients. MATERIAL AND METHODS This study included 242 patients attended by 45 doctors. Self-reported doctors' empathy ability was measured at patient admission (T1), and patient-reported physician empathy was measured 3 months later (T2). Patient anxiety, general self-efficacy, sleep, and inflammatory factor (IL-6) were measured on T1 and T2. Pearson correlation analysis was used to assess the relationships between self-reported doctor empathy ability and patient indices on T1 and T2. The relationships between anxiety, sleep quality, self-efficacy, IL-6, and patient-reported physician empathy were measured by Pearson correlation analysis and structural equation modeling. RESULTS On T1, no significant correlation was reported between self-reported doctors' empathy ability and indices of the patients (P>0.05). On T2, self-reported doctors' empathy ability was significantly positively correlated with patient sleep and self-efficacy (P<0.01), and significantly negatively correlated with patient anxiety and IL-6 (P<0.01). Moreover, on T2, patient-reported physician empathy was negatively correlated with anxiety and IL-6 and was positively correlated with self-efficacy and sleep quality. The effect of patient-reported physician empathy on IL-6 was mediated by anxiety, sleep quality, and self-efficacy. CONCLUSIONS The anxiety, self-efficacy, and sleep quality of UC patients had mediating effects in the relationship between patient-reported physician empathy and IL-6.


Assuntos
Colite Ulcerativa/psicologia , Pacientes/psicologia , Relações Médico-Paciente , Adulto , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , China , Empatia , Feminino , Humanos , Inflamação , Interleucina-6/análise , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Médicos , Autoeficácia , Sono/fisiologia , Inquéritos e Questionários
6.
Gerontology ; 65(5): 465-473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31212285

RESUMO

Anxiety disorders are common, yet clinically underrecognized in late life, with estimated prevalence rates ranging from 1.2 to 15%. They are highly comorbid with depression, sleep disorders, and substance use disorders, may accelerate cognitive decline, and potentially catalyze morbidity and mortality risk in the elderly. Thus, a more detailed knowledge about the underlying mechanisms of late-life anxiety disorders is urgently warranted. Age-related genetic, neuroimaging, neuroendocrine, and neuropsychological markers as well as late-life specific psychosocial aspects, particularly loss and isolation, have been identified as prominent pathogenetically relevant and thus potentially targetable factors. Personalized treatments based on individual biological and biographic markers, innovative therapeutic approaches, and preventive strategies have great potential to alleviate the high individual and societal burden of late-life anxiety disorders.


Assuntos
Envelhecimento/psicologia , Transtornos de Ansiedade/psicologia , Idoso , Ansiedade/psicologia , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Envelhecimento Cognitivo/psicologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Comorbidade , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/psicologia , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/psicologia , Isolamento Social/psicologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
7.
Transl Psychiatry ; 9(1): 170, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213596

RESUMO

There is growing evidence for GABA and glutamate-glutamine dysfunction in the pathogenesis of mood and anxiety disorders. It is important to study this pathology in the early phases of the illness in order to develop new approaches to secondary prevention. New magnetic resonance spectroscopy (MRS) measures allow determining glutamine, the principal metabolite of synaptic glutamate that is directly related to glutamate levels in the synaptic cleft, as well as glutamate and GABA. In contrast to previous investigations, this study used community-based recruitment methods and a combined categorical and dimensional approach to psychopathology. In the study protocol, neuroticism was defined as the primary outcome. Neuroticism shares a large proportion of its genetic variance with mood and anxiety disorders. We examined young adult participants recruited from the general population in a cross-sectional study using 3-T 1H-MRS with one voxel in the left dorsolateral prefrontal cortex (DLPFC). The total sample of N = 110 (61 females) included 18 individuals suffering from MDD and 19 individuals suffering from DSM-IV anxiety disorders. We found that glutamine and glutamine-to-glutamate ratio were correlated with neuroticism in the whole sample (r = 0.263, p = 0.005, and n = 110; respectively, r = 0.252, p = 0.008, and n = 110), even when controlling for depression and anxiety disorder diagnoses (for glutamine: beta = 0.220, p = 0.047, and n = 110). Glutamate and GABA were not significantly correlated with neuroticism (r = 0.087, p = 0.365, and n = 110; r = -0.044, p = 0.645, and n = 110). Lack of self-confidence and emotional instability were the clinical correlates of glutamate-glutamine dysfunction. In conclusion, this study suggests that prefrontal glutamine is increased in early phases of mood and anxiety disorders. Further understanding of glutamate-glutamine dysfunction in stress-related disorders may lead to new therapeutic strategies to prevent and treat these disorders.


Assuntos
Transtornos de Ansiedade/metabolismo , Transtorno Depressivo Maior/metabolismo , Glutamina/metabolismo , Neuroticismo , Córtex Pré-Frontal/metabolismo , Adulto , Transtornos de Ansiedade/diagnóstico por imagem , Estudos Transversais , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Ácido Glutâmico/metabolismo , Humanos , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Espectroscopia de Prótons por Ressonância Magnética , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
8.
Med Sci Monit ; 25: 4322-4332, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31180069

RESUMO

BACKGROUND We previously discovered that 3 long non-coding RNAs (lncRNAs) NONHSAT089447, NONHSAT021545, and NONHSAT041499 were differentially expressed in the peripheral blood of patients with schizophrenia, in comparison to those in normal healthy controls. In this study, we conducted bioinformatic analysis of these 3 lncRNAs and the regulatory role of lncRNA NONHSAT089447 in the dopamine signaling pathway in patients with schizophrenia. MATERIAL AND METHODS There lncRNAs in peripheral blood mononuclear cells (PBMCs) were screened using microarray analysis. Pearson's correlation analysis was performed to assess the levels of co-expressed mRNAs of respective lncRNAs. The Database for Annotation, Visualization and Integrated Discovery (DAVID) software was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes or Genomes (KEGG) enrichment analysis for these lncRNAs. Human neuroblastoma cell lines (SK-N-SH) were cultured and treated with dopamine or olanzapine (OLP), or transfected with siRNA targeting NONHSAT089447 or plasmid expressing NONHSAT089447. Levels of lncRNAs were detected by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Then, mRNA and protein expression of the dopamine receptors DRD1, DRD2, DRD3, DRD4, and DRD5 were measured by RT-PCR and western blot analysis, respectively. RESULTS OLP treatment significantly inhibited the expression of NONHSAT089447. Knockdown of NONHSAT089447 by siRNA decreased DRD3 and DRD5 expression, while overexpression of NONHSAT089447 significantly upregulated expression of DRD3 and DRD5. Western blot analysis confirmed that levels of NONHSAT089447 regulated downstream DRD signaling. CONCLUSIONS Our results revealed that the lncRNA NONHSAT089447 participated in the dopamine signaling pathway via upregulation of DRDs.


Assuntos
Dopamina/metabolismo , RNA Longo não Codificante/metabolismo , Esquizofrenia/metabolismo , Adulto , Transtornos de Ansiedade/metabolismo , Linhagem Celular Tumoral , Biologia Computacional/métodos , Transtorno Depressivo Maior/metabolismo , Dopamina/genética , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Esquizofrenia/genética , Transdução de Sinais/genética
9.
Int J Mol Sci ; 20(11)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167373

RESUMO

Clinical studies show a significant association of childhood adversities and FK506-binding protein 5 (FKBP5) polymorphisms on increasing the susceptibility for neuropsychiatric disorders. However, the mechanisms by which early life stress (ELS) influences FKBP5 actions have not been fully elucidated. We hypothesized that interactions between ELS and high FKBP5 induce phenotypic changes that correspond to underlying molecular changes in the brain. To test this, we exposed newborn mice overexpressing human FKBP5 in the forebrain, rTgFKBP5, to ELS using a maternal separation. Two months after ELS, we observed that ELS increased anxiety levels, specifically in mice overexpressing FKBP5, an effect that was more pronounced in females. Biochemically, Protein kinase B (AKT) phosphorylation was reduced in the dorsal hippocampus in rTgFKBP5 mice, which demonstrates that significant molecular changes occur as a result of ELS when FKBP5 levels are altered. Taken together, our results have a significant impact on our understanding mechanisms underlying the gene x environment interaction showing that anxiety and AKT signaling in the hippocampus were affected by the combination of ELS and FKBP5. An increased knowledge of the molecular mechanisms underlying these interactions may help determine if FKBP5 could be an effective target for the treatment of anxiety and other mood-related illnesses.


Assuntos
Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/metabolismo , Hipocampo/metabolismo , Acontecimentos que Mudam a Vida , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Estresse Psicológico , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Ansiedade , Transtornos de Ansiedade/diagnóstico , Comportamento Animal , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Genótipo , Hipocampo/fisiopatologia , Humanos , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Fosforilação , Ligação Proteica , Avaliação de Sintomas , Proteínas de Ligação a Tacrolimo/genética
10.
PLoS One ; 14(5): e0216000, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31116735

RESUMO

Hair is an emerging biological matrix in which to measure chronic HPA axis activity, offering a longer term view into an animal's life. We explored effects of exogenous (e.g. lifestyle, medications, social environment) and endogenous (e.g. disease, behaviour) stressors on hair cortisol concentration (HCC) in a population of Border Collies (BCs). Owners of BCs were recruited and reported their dog's lifestyle, clinical history, anxiety-related behaviour, and collected a white hair sample from their dog's dorsal neck region. HCC was determined using established methods with a commercial cortisol assay kit. Samples from 135 BCs were analysed, with 91 healthy controls and 44 diagnosed with epilepsy as a model disease. Factors associated with higher HCC included psychosocial stressors (living with three or more other dogs) and lifestyle (engaging in competitive flyball); while factors associated with lower HCC included anxiety (stranger-directed and non-social), health (epilepsy diagnosis, with number of seizures to date negatively correlated with HCC) and medication (certain anti-epileptic drugs were associated with elevated or reduced HCC). These novel results highlight the potential of chronic stress with frequent or persisting HPA-axis hyperactivity leading to a state of hypocortisolism, and the need to consider stressor recency and recurrence when interpreting HCC data.


Assuntos
Cabelo/metabolismo , Cabelo/fisiologia , Hidrocortisona/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Animais , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Cães , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiologia
11.
Psychiatry Res ; 272: 756-764, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30832196

RESUMO

Several studies suggest that anxiety disorders (AD) involve dysregulation of the autonomic nervous system (ANS) and hypothalamic-pituitary (HPA) axis. However, it is unknown if alterations in these biological systems are premorbid markers of AD risk or a state-dependent feature of anxiety. This study examined ANS and HPA-axis response to a laboratory stressor in healthy child offspring of parents with (n = 55) and without (n = 98) a history of AD. High frequency heart rate variability (HF-HRV) was assessed during sitting and standing baseline conditions and during a speech task where participants remained standing. Salivary cortisol was measured at baseline and at 15, 30, 45 and 60 min post-speech. Subjective anxiety was assessed with a visual analogue scale. Children of parents with AD displayed reduced HRV and a blunted cortisol response to the speech task compared to children of non-anxious parents. No risk group effect was found for anxiety ratings. These preliminary data suggest that healthy children of anxious parents exhibit altered stress reactivity to an acute laboratory stressor. Further research is needed to confirm findings and identify mechanisms that may account for altered self-regulation processes to a stressor in children at familial risk for AD.


Assuntos
Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/psicologia , Filho de Pais Incapacitados/psicologia , Pais/psicologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Adolescente , Transtornos de Ansiedade/diagnóstico , Criança , Feminino , Frequência Cardíaca/fisiologia , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Saliva/metabolismo , Estresse Psicológico/diagnóstico
12.
Behav Pharmacol ; 30(2 and 3-Spec Issue): 187-200, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30844962

RESUMO

Stress is a nonspecific response of the body to any demand imposed upon it, disrupting the body homoeostasis and manifested with symptoms such as anxiety, depression or even headache. These responses are quite frequent in the present competitive world. The aim of this review is to explore the effect of stress on gut microbiota. First, we summarize evidence of where the microbiota composition has changed as a response to a stressful situation, and thereby the effect of the stress response. Likewise, we review different interventions that can modulate microbiota and could modulate the stress according to the underlying mechanisms whereby the gut-brain axis influences stress. Finally, we review both preclinical and clinical studies that provide evidence of the effect of gut modulation on stress. In conclusion, the influence of stress on gut microbiota and gut microbiota on stress modulation is clear for different stressors, but although the preclinical evidence is so extensive, the clinical evidence is more limited. A better understanding of the mechanism underlying stress modulation through the microbiota may open new avenues for the design of therapeutics that could boost the pursued clinical benefits. These new designs should not only focus on stress but also on stress-related disorders such as anxiety and depression, in both healthy individuals and different populations.


Assuntos
Microbioma Gastrointestinal/fisiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/metabolismo , Ansiedade , Transtornos de Ansiedade/metabolismo , Encéfalo/metabolismo , Depressão , Transtorno Depressivo/metabolismo , Humanos , Estresse Psicológico/microbiologia
13.
J Affect Disord ; 245: 806-811, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30699863

RESUMO

BACKGROUND: Anxious youth are at risk for negative peer interactions including peer victimization, and for suicidal ideation. However, data about the pattern of association between these two factors are scarce. In this study we examined the association between negative peer interactions and suicidal ideation in a sample of children and adolescents with anxiety disorders, and whether oxytocin, which has been shown to enhance the impact of social events, moderates the impact of negative peer interactions on suicidal ideation. METHOD: Participants were 168 youths with primary anxiety disorders. All participants were assessed with semi-structured diagnostic interviews, and with self-report measures of suicidal ideation, negative peer interactions, anxiety, and depression. The anxious youths' salivary oxytocin levels were measured with immunoassay. RESULTS: Thirty percent of the anxious youths reported suicidal ideation, with suicidal ideation severity associated with negative peer social interactions and depressive symptoms. Consistent with past data indicating that oxytocin enhances the impact of social events, the association between peer negative social interactions and suicidal ideation was stronger in youths with high oxytocin levels than in youths with low levels (i.e., moderation). LIMITATIONS: Assessment focused on suicidal ideation and data on suicidal behavior were not available. Limitations inherent to immunoassay measurement of peripheral oxytocin levels are noted. CONCLUSION: Negative peer interactions are associated with suicidal ideation in youth with anxiety disorders, and the association is stronger in youth with high oxytocin levels.


Assuntos
Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/psicologia , Relações Interpessoais , Ocitocina/metabolismo , Grupo Associado , Ideação Suicida , Adolescente , Transtornos de Ansiedade/complicações , Bullying , Criança , Vítimas de Crime , Depressão/complicações , Depressão/metabolismo , Depressão/psicologia , Feminino , Humanos , Masculino , Saliva/metabolismo , Autorrelato
14.
Behav Brain Res ; 364: 366-373, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30753872

RESUMO

Hippocampal theta activity is a prominent slow (4-12 Hz) oscillatory activity pattern generated in the mammalian hippocampal formation. Based on evidence that anxiolytic drugs consistently decrease the frequency of hippocampal theta activity in rodents, hippocampal theta has been linked to anxiety states, leading to the influential theta suppression model of anxiolysis. Surprisingly, very few studies have examined whether hippocampal theta frequency relates to individual or sex differences in anxiety-like behaviour. Here, male and female rats were tested on the elevated plus maze (EPM) to quantify levels of defensive, anxiety-like behaviours. Females exhibited higher levels of open arm exploration (open arm entries and open arm time) compared to males, suggestive of reduced anxiety in females. Subsequently, reticular-elicited hippocampal theta activity was characterized in the same rats under deep urethane anesthesia. There was no sex difference in theta frequency over a range of stimulation intensities. Further, there were no significant correlations between behavioural measures of anxiety in the EPM and theta frequency among individual animals. Theta frequency did, however, decrease following systemic administration of the clinically-used anxiolytic agent buspirone (10 mg/kg). Together, these results suggest that theta frequency does not relate to levels of anxiety-like behaviours in the EPM in male and female rats, challenging the predictive validity of hippocampal theta activity as an index of anxiety in rodents.


Assuntos
Ansiedade/fisiopatologia , Hipocampo/fisiologia , Ritmo Teta/fisiologia , Animais , Ansiolíticos/farmacologia , Ansiedade/metabolismo , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Buspirona/farmacologia , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Long-Evans , Fatores Sexuais , Ritmo Teta/efeitos dos fármacos
15.
Transl Psychiatry ; 9(1): 33, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670681

RESUMO

Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT-/-) have increased baseline anxiety behaviors, SERT+/- rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT+/- model. Here we sought to determine if SERT+/- or SERT-/-, compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT-/- rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT+/- (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT+/- rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT-/- and SERT+/- rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.


Assuntos
Tonsila do Cerebelo/metabolismo , Transtornos de Ansiedade/metabolismo , Ansiedade/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Comportamento Animal/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Masculino , Proteínas de Ligação a RNA/genética , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo
16.
Metab Brain Dis ; 34(2): 527-535, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30604028

RESUMO

Growing evidence support the role of vitamin D in brain function and behavior. This study investigated the relationship between 25-hydroxyvitamin D3 [25(OH)D3] levels, biochemical profile and symptoms of depression and anxiety in healthy individuals. Symptoms of depression were assessed by the Beck Depression Inventory (BDI) and anxiety was evaluated with the State-Trait Anxiety Inventory (STAI). Our sample included 36 individuals, mostly women 27(75%), 36.39 ± 9.72 years old, non-smokers 31(86.1%), body mass index of 26.57 ± 3.92 kg/m2, 27.95 ± 7.50% body fat. Participants were divided into those with 25(OH)D3 levels lower than 40 ng/mL (mean 28.16 ± 7.07) and equal or higher than 40 ng/mL (mean 53.19 ± 6.32). Those with lower 25(OH)D3 had higher levels of triacylglycerol, triacylglycerol/high density lipoprotein (HDL) ratio, high glucose and homeostatic model assessment of insulin resistance (HOMA-IR) index. No changes were observed in sociodemographic variables, body composition, inflammatory parameters and cortisol. Additionally, in the groups with low and high 25(OH)D3 levels, STAI state, STAI trait and BDI scores were not statistically different. Levels of 25(OH)D3 were inversely and independently associated with glucose and HOMA-IR, but not associated with triacylglycerol, depression and anxiety scores. Lower levels of 25(OH)D3 were associated with dysfunction in glucose metabolism but not with depression and anxiety in healthy individuals.


Assuntos
Transtornos de Ansiedade/metabolismo , Ansiedade/metabolismo , Calcifediol/metabolismo , Depressão/metabolismo , Adulto , Transtorno Depressivo/complicações , Transtorno Depressivo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Deficiência de Vitamina D/complicações , Vitaminas/metabolismo
17.
Rev Neurosci ; 30(3): 325-337, 2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-30179855

RESUMO

Pharmacological and molecular imaging studies in anxiety disorders have primarily focused on the serotonin system. In the meantime, dopamine has been known as the neurotransmitter of reward for 60 years, particularly for its action in the nervous terminals of the mesocorticolimbic system. Interest in the mediation by dopamine of the well-known brain aversion system has grown recently, particularly given recent evidence obtained on the role of D2 dopamine receptors in unconditioned fear. However, it has been established that excitation of the mesocorticolimbic pathway, originating from dopaminergic (DA) neurons from the ventral tegmental area (VTA), is relevant for the development of anxiety. Among the forebrain regions innervated by this pathway, the amygdala is an essential component of the neural circuitry of conditioned fear. Current findings indicate that the dopamine D2 receptor-signaling pathway connecting the VTA to the basolateral amygdala modulates fear and anxiety, whereas neural circuits in the midbrain tectum underlie the expression of innate fear. The A13 nucleus of the zona incerta is proposed as the origin of these DA neurons projecting to caudal structures of the brain aversion system. In this article we review data obtained in studies showing that DA receptor-mediated mechanisms on ascending or descending DA pathways play opposing roles in fear/anxiety processes. Dopamine appears to mediate conditioned fear by acting at rostral levels of the brain and regulate unconditioned fear at the midbrain level.


Assuntos
Transtornos de Ansiedade/metabolismo , Dopamina/metabolismo , Medo/fisiologia , Área Tegmentar Ventral/metabolismo , Animais , Ansiedade/metabolismo , Humanos , Recompensa
18.
Behav Brain Res ; 356: 107-119, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30118773

RESUMO

Previous studies showed that chronic treatment with corticosterone facilitates elevated T-maze (ETM) inhibitory avoidance and a step-down avoidance task, responses that have been used to investigate aversive conditioning and memory processes. On the other hand, chronic corticosterone does not alter ETM escape from the open arms. The purpose of the present study was to further investigate the effects of chronic corticosterone treatment (200 mg pellets, 21-day release) in an animal model of anxiety that does not involve aversive conditioning: the light/dark transition model. We also investigated the pattern of ΔFosB immunoreactivity (ΔFosB-ir) in different brain regions. To examine how treatment with chronic corticosterone interferes with CRFR1 expression we measured CRFR1 in the same brain structures that exhibited increased ΔFosB-ir. Results showed that chronic treatment with corticosterone did not alter behavioral measurements performed in the light/dark transition model. On the other hand, ΔFosB-ir was increased in several structures that modulate aversive conditioning: the cingulate cortex, the ventro and dorsolateral septum, the amygdala, the paraventricular, dorsomedial and ventromedial hypothalamus, the periaqueductal grey matter, the dorsal raphe, and the median raphe nucleus. Chronic treatment with corticosterone also increased CRFR1-immunoreactivity in the ventrolateral septum, central amygdala, dorsomedial hypothalamus, ventral region of the dorsal raphe and median raphe. These results contribute to a better understanding of the behavioral and neurobiological alterations induced by chronic exposure to glucocorticoids.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Animais , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Aprendizagem da Esquiva/fisiologia , Encéfalo/metabolismo , Corticosterona/farmacologia , Modelos Animais de Doenças , Reação de Fuga/fisiologia , Masculino , Memória , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/imunologia , Ratos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/imunologia , Estresse Psicológico/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-30201454

RESUMO

BACKGROUND: Depression, anxiety and somatoform disorders are all more prevalent in women than in men. However, specific biological mechanisms contributing to such sex differences remain unknown. Serotonergic pathways are involved in mood and behavior regulation and thus have been suggested to be altered in several psychiatric disorders. The serotonin transporter (SERT), encoded by SLC6A4 gene, has received major attention due to its crucial role in serotonergic transmission. METHODS: 148 monozygotic twin subjects were assessed for (i) lifetime categorical diagnosis of anxious-depressive disorders, following SCID-I-based DSM-IV criteria, and (ii) current psychiatric symptomatology, from a dimensional approach, by means of the Brief Symptom Inventory (BSI). SLC6A4 gene methylation was analyzed by means of Infinium HumanMethylation450 in a subset of the sample. CpG-specific methylation at the promoter region of SLC6A4 gene was further analyzed by means of pyrosequencing technology in the total sample. RESULTS: SLC6A4 methylation was found to be significantly higher in women when compared to men independent of DSM-IV diagnosis. SLC6A4 methylation was further associated with the BSI-derived somatization dimension. CONCLUSIONS: Female hypermethylation of a discrete region located within SLC6A4 promoter region could underlie differential SERT expression in women when compared to men and could be one of the causative mechanisms by which women exhibit increased prevalence of somatic symptoms.


Assuntos
Metilação de DNA , Epigênese Genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Caracteres Sexuais , Transtornos Somatoformes/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Ilhas de CpG , Transtorno Depressivo/genética , Transtorno Depressivo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Escalas de Graduação Psiquiátrica , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transtornos Somatoformes/genética , Gêmeos Monozigóticos , Adulto Jovem
20.
Psychopharmacology (Berl) ; 236(1): 239-250, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30238131

RESUMO

N-Methyl D-aspartate receptors (NMDAR) are central mediators of glutamate actions underlying learning and memory processes including those required for extinction of fear and fear-related behaviors. Consistent with this view, in animal models, antagonists of NMDAR typically impair fear extinction, whereas partial agonists have facilitating effects. Promoting NMDAR function has thus been recognized as a promising strategy towards reduction of fear symptoms in patients suffering from anxiety disorders and post-traumatic disorder (PTSD). Nevertheless, application of these drugs in clinical trials has proved of limited utility. Here we summarize recent advances in our knowledge of NMDAR pharmacology relevant for fear extinction, focusing on molecular, cellular, and circuit aspects of NMDAR function as they relate to fear extinction at the level of behavior and cognition. We also discuss how these advances from animal models might help to understand and overcome the limitations of existing approaches in human anxiety disorders and how novel, more specific, and personalized approaches might help advance future therapeutic strategies.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/fisiologia , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Transdução de Sinais/efeitos dos fármacos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/metabolismo
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