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1.
J Affect Disord ; 277: 772-778, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065816

RESUMO

BACKGROUND: The wearing of respiratory protective devices (RPDs) correctly and continually in situations where people are at risk of respiratory infections is crucial for infection prevention. Certain people are poorly compliant with RPDs due to RPD-related annoyance, including respiratory discomfort. We hypothesized that individuals vulnerable to panic attacks are included in this group. No published studies on this topic are available. The evidence for our hypothesis was reviewed in this study as a starting point for future research. METHODS: We selected a set of experimental studies that measured the respiratory physiological burden in RPD wearers through objective and validated methods. We conducted a bibliographic search of publications in the PubMed database (January 2000-May 2020) to identify representative studies that may be of interest for panic respiratory pathophysiology. RESULTS: Five studies were included. Wearing RPDs exerted significant respiratory effects, including increased breathing resistance, CO2 rebreathing due to CO2 accumulation in the RPD cavity, and decreased inhaled O2 concentration. We discussed the implications of these effects on the respiratory pathophysiology of panic. LIMITATIONS: Most studies had a small sample size, with a preponderance of young participants. Different methodologies were used across the studies. Furthermore, differences in physical responses between wearing RPDs in experimental settings or daily life cannot be excluded. CONCLUSIONS: This research supports the idea that panic-prone individuals may be at higher risk of respiratory discomfort when wearing RPDs, thereby reducing their tolerance for these devices. Strategies to decrease discomfort should be identified to overcome the risk of poor compliance.


Assuntos
Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Transtorno de Pânico/fisiopatologia , Pneumonia Viral/prevenção & controle , Transtornos Respiratórios/fisiopatologia , Respiração , Dispositivos de Proteção Respiratória/efeitos adversos , Resistência das Vias Respiratórias , Betacoronavirus , Dióxido de Carbono/metabolismo , Humanos , Oxigênio/metabolismo , Transtorno de Pânico/metabolismo , Transtorno de Pânico/psicologia , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/metabolismo , Transtornos Respiratórios/psicologia , Rinomanometria , Espirometria
2.
Psychopharmacology (Berl) ; 237(4): 1063-1079, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31919563

RESUMO

RATIONALE: The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals. OBJECTIVES: This study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception. METHODS: A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH. RESULTS: The morphological procedures demonstrated distribution of labelled CB1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB1 receptor antagonist AM251 (100 pmol) in the VMH. CONCLUSION: These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB1 receptor-endocannabinoid signalling mechanism in VMH.


Assuntos
Canabidiol/toxicidade , Medo/fisiologia , Medição da Dor/métodos , Transtorno de Pânico/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Canabidiol/administração & dosagem , Medo/efeitos dos fármacos , Medo/psicologia , Injeções Intraventriculares , Masculino , N-Metilaspartato/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/psicologia , Transtorno de Pânico/induzido quimicamente , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos
3.
Depress Anxiety ; 36(12): 1173-1181, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31374578

RESUMO

BACKGROUND: Anxiety disorders including panic disorder (PD) are the most prevalent psychiatric diseases leading to high disability and burden in the general population. Acute panic attacks are distinctive for PD but also frequent in other anxiety disorders. The neurobiology or specific molecular changes leading to and present during panic attacks are insufficiently known so far. METHODS: In the present pilot study, we investigated dynamic metabolomic and gene expression changes in peripheral blood of patients with PD (n = 25) during two exposure-induced acute panic attacks. RESULTS: The results show that the metabolite glyoxylate was dynamically regulated in peripheral blood. Additionally, glyoxylate levels were associated with basal anxiety levels and showed gender-related differences at baseline. As glyoxylate is part of the degradation circuit of cholecystokinin, this suggests that this neuropeptide might be directly involved in exposure-induced panic attacks. Only gene expression changes of very small magnitude were observed in this experimental setting. CONCLUSIONS: From this first metabolome and gene expression study in exposure-induced acute panic attacks in PD we conclude that metabolites can potentially serve as dynamic markers for different anxiety states. However, these findings have to be replicated in cohorts with greater sample sizes.


Assuntos
Regulação da Expressão Gênica , Metaboloma , Transtorno de Pânico/sangue , Transtorno de Pânico/genética , Adulto , Ansiedade/sangue , Ansiedade/genética , Ansiedade/metabolismo , Colecistocinina/sangue , Colecistocinina/metabolismo , Feminino , Glioxilatos/sangue , Glioxilatos/metabolismo , Humanos , Masculino , Transtorno de Pânico/metabolismo , Projetos Piloto , Prevalência , Caracteres Sexuais
4.
Psychoneuroendocrinology ; 101: 216-222, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30471570

RESUMO

The probable implication of testosterone in the neurobiology of anxiety disorders, and particularly panic disorder (PD), is poorly studied. We explored for potential differences concerning testosterone (T) plasma levels and the ratio testosterone/cortisol (T/C) between medication-free, consecutively-referred patients with acute exacerbation of PD comorbid with agoraphobia (PDA) (N = 40; females = 24; age = 31.4 ± 7.1 years) and healthy controls (N = 80; females = 48; matched for age). Moreover, we investigated for potential associations of T levels and T/C ratio with the severity of acute PDA psychopathology in the patients of the sample. Psychometric measures included panic attacks' number during last three weeks (PA-21days), the Agoraphobic Cognitions Questionnaire (ACQ) and the Hamilton Anxiety Rating Scale (HARS). Male patients -but not female ones- demonstrated significantly lower T levels compared to controls. Moreover, in male patients, a significant inverse association emerged between T/C ratio and PA-21days, so that lower T/C ratio is associated with significantly more panic attacks. On the contrary, female patients demonstrated significant positive associations: (a) between T levels and PDA-related pathological cognitions (ACQ); (b) between the T/C ratio and both PA-21days and anxiety symptoms' severity (HARS). The results of the study suggest that testosterone is significantly associated to the severity of clinical manifestations of acute panic disorder, although in a different fashion concerning the two genders.


Assuntos
Transtorno de Pânico/etiologia , Transtorno de Pânico/metabolismo , Testosterona/metabolismo , Doença Aguda , Adulto , Agorafobia/complicações , Agorafobia/metabolismo , Agorafobia/fisiopatologia , Ansiedade , Transtornos de Ansiedade , Comorbidade , Feminino , Humanos , Hidrocortisona/análise , Hidrocortisona/sangue , Masculino , Pânico , Transtorno de Pânico/fisiopatologia , Escalas de Graduação Psiquiátrica , Psicometria/métodos , Fatores Sexuais , Testosterona/análise , Testosterona/sangue
5.
Transl Psychiatry ; 8(1): 226, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30341278

RESUMO

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.


Assuntos
Encéfalo/metabolismo , Medo/fisiologia , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Norepinefrina/fisiologia , Transtorno de Pânico/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Adulto , Alelos , Ansiedade/genética , Ansiedade/metabolismo , Encéfalo/fisiopatologia , Mapeamento Encefálico , Condicionamento Clássico , Extinção Psicológica , Feminino , Variação Genética , Humanos , Imagem por Ressonância Magnética , Masculino , MicroRNAs/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Transtorno de Pânico/genética , Transtorno de Pânico/fisiopatologia , Polimorfismo de Nucleotídeo Único , Regulação para Cima
6.
Psychoneuroendocrinology ; 94: 31-37, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29754003

RESUMO

BACKGROUND: An attenuated responsivity of the hypothalamus-hypophysis-adrenal (HPA) axis upon challenge and an increased risk for cardiac events are relatively consistent findings in panic disorder (PD) patients. Due to cytokine-HPA interactions, an altered HPA-axis responsivity may be accompanied by altered cytokine concentrations. Immunological reactions under stress might be considered the missing link for explaining an increased cardiac risk. This study analyzed stress-induced cytokine levels in PD patients. METHODS: A total of n = 32 PD patients and n = 32 healthy control individuals performed the Trier Social Test (TSST). Blood sample collection accompanied the TSST for the collection of cortisol and pro- (IL-6, TNF-α) and anti-inflammatory cytokines (IL-10). Established self-report questionnaires were handed out for the clinical characterization and the assessment of subjective levels of distress during testing. Repeated measures ANCOVA were conducted to evaluate main effects of time or group and time x group interaction effects. Additional ANCOVAS with disease severity as between-subjects factor (healthy, borderline, mild, moderate, severe) took global panic severity into account. Pearson correlation analyses were carried out to test for an association of panic specific symptoms and peak cytokine release. RESULTS: The TSST resulted in a significantly increased secretion of cortisol, IL-6 and IL-10. The data analysis further revealed a significant time x group interaction effect for cortisol and IL-10. Compared to the healthy volunteers, the PD patients showed significantly higher baseline and challenged IL-10 concentrations but lower challenged cortisol concentrations. Mildly and moderately affected patients showed the highest levels of IL-10 compared to the healthy individuals. There were no differential secretion patterns of IL-6 and TNF-α between both groups in the course of the TSST. The peak IL-6 release was found to be significantly associated with global disease severity. CONCLUSION: We found evidence for altered levels of cytokines with primarily anti-inflammatory properties in PD patients under baseline and a psychosocial stress condition. The results provide tentative evidence for a low-grade inflammatory process in PD patients, possibly representing a missing link factor between PD diagnosis and the increased risk for cardiac disease.


Assuntos
Citocinas/metabolismo , Transtorno de Pânico/metabolismo , Estresse Psicológico/metabolismo , Adulto , Estudos de Casos e Controles , Citocinas/análise , Citocinas/sangue , Feminino , Humanos , Hidrocortisona/análise , Sistema Hipotálamo-Hipofisário/metabolismo , Interleucina-10 , Interleucina-6 , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/sangue , Sistema Hipófise-Suprarrenal/metabolismo , Escalas de Graduação Psiquiátrica , Saliva/química , Estresse Psicológico/psicologia , Fator de Necrose Tumoral alfa
7.
Neurosci Res ; 137: 49-56, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29550536

RESUMO

Reported findings on reactivity to stress of the sympathetic-adreno-medullar (SAM) and hypothalamic-pituitary-adrenal (HPA) systems in panic disorder (PD) are very variable. This inconsistency may be explained by differences in treatment exposure, illness duration and emotion regulation strategies. The present study examined the reactivity to mental stress of the SAM and HPA axes in a sample of first episode, drug naïve patients with PD which avoids confounds of medications exposure and illness chronicity. Activation of the SAM axis was evaluated by dosage of salivary alpha-amylase (sAA) and heart rate. Activation of the HPA axis was tested by dosage of salivary cortisol. Psychological assessments were done by the Self-Rating Depression Scale, the Self-Rating Anxiety Scale, the State-Trait Anxiety Inventory, the Cope Orientation to Problems Experienced (COPE) Inventory and the 16 Personality Factor Questionnaire (16PF). Patients showed reduced sAA stress reactivity, higher baseline cortisol levels and a more rapid decrease in stress cortisol levels as compared with controls. A significant correlation was found between active coping strategies and cortisol levels (response to stress). The findings suggest that blunted SAM stress reactivity and a rapid decrease in stress cortisol levels reflect traits that may enhance vulnerability to psychopathology in patients with PD.


Assuntos
Hidrocortisona/metabolismo , Transtorno de Pânico/metabolismo , Transtorno de Pânico/fisiopatologia , alfa-Amilases Salivares/metabolismo , Estresse Psicológico/fisiopatologia , Adaptação Psicológica/fisiologia , Adolescente , Adulto , Feminino , Frequência Cardíaca/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/enzimologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Transtorno de Pânico/enzimologia , Sistema Hipófise-Suprarrenal/enzimologia , Sistema Hipófise-Suprarrenal/metabolismo , Escalas de Graduação Psiquiátrica , Saliva/enzimologia , Estresse Psicológico/complicações , Adulto Jovem
8.
Brain Behav Immun ; 67: 36-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28736033

RESUMO

BACKGROUND: While disruption of acid-base homeostasis has been pathoetiologically implicated in panic disorder (PD), the mechanism by which pH imbalance is translated to panic pathophysiology is poorly understood. Recently, in a translational rodent model of PD, we reported a role of microglial acid sensing G-protein coupled receptor, T cell death associated gene-8 (TDAG8) in panic-associated behavior and physiology. However, the clinical validity of the TDAG8 receptor has not been investigated. OBJECTIVE: To assess TDAG8 in PD, we evaluated TDAG8 receptor expression in adolescents and young adults with PD and healthy comparison subjects. METHODS: Relative expression of TDAG8 mRNA was determined in peripheral blood mononuclear cells from patients with PD, and compared to expression in healthy subjects. Linear models were utilized to evaluate the relationship between TDAG8 expression and panic disorder symptom severity scale (PDSS) score as well as other potential explanatory variables (e.g., CRP, body mass index, sex, age). Models were refined based on the estimated parameter significance, evidence of omitted variable bias and Bayesian/Akaike information criteria. RESULTS: Relative to healthy comparison subjects (n=17), expression of TDAG8 mRNA was significantly increased in patients with PD (n=15) (1.60±0.65 vs. 1.01±0.50, p=0.008). TDAG8 mRNA expression predicted PD symptom severity in a fixed effect model incorporating age and sex (p=0.003). CONCLUSIONS: Collectively, our results suggest greater TDAG8 expression in patients with PD compared to healthy subjects, and directly link TDAG8 expression and the severity of the PD symptoms. Further investigation of the TDAG8 receptor in panic pathophysiology is warranted.


Assuntos
Transtorno de Pânico/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Adolescente , Adulto , Proteína C-Reativa/metabolismo , Feminino , Humanos , Masculino , Projetos Piloto , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Adulto Jovem
9.
Neuroscience ; 369: 336-349, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29183829

RESUMO

Using an innovative approach to study the neural bases of psychiatric disorders, this study investigated the behavioral, morphological and pharmacological bases of panic attack-induced responses in a prey-versus-coral snake paradigm. Mesocricetus auratus was chronically treated with intraperitoneal administration of the selective serotonin uptake inhibitor paroxetine or the gamma aminobutyric acid (GABA)/benzodiazepine receptor agonist alprazolam at three different doses and were then confronted with a venomous coral snake (Micrurus frontalis, Reptilia, Elapidae). The threatened rodents exhibited defensive attention, flat back approaches, defensive immobility, and escape defensive responses in the presence of the venomous snake, followed by increases in Fos protein in limbic structure neurons. Chronic administration of both paroxetine and alprazolam decreased these responses with morphological correlates between the panicolytic effect of both drugs administered at the highest dose and decreases in Fos protein-immunolabeled perikarya found in the amygdaloid complex, hypothalamus and periaqueductal gray matter columns, which are structures that make up the encephalic aversion system. These findings provide face, construct and predictive validities of this new experimental model of anxiety- and panic attack-like behavioral responses displayed by threatened prey confronted with venomous coral snakes.


Assuntos
Ansiedade , Modelos Animais , Transtorno de Pânico , Pânico , Comportamento Predatório , Alprazolam/farmacologia , Animais , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiedade/patologia , Relação Dose-Resposta a Droga , Elapidae , Reação de Fuga/fisiologia , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/metabolismo , Sistema Límbico/patologia , Masculino , Mesocricetus , Pânico/efeitos dos fármacos , Pânico/fisiologia , Transtorno de Pânico/dietoterapia , Transtorno de Pânico/metabolismo , Transtorno de Pânico/patologia , Paroxetina/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo
10.
Transl Psychiatry ; 7(12): 1287, 2017 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-29249830

RESUMO

Panic disorder (PD) affects about four million Europeans, with women affected twice as likely as men, causing substantial suffering and high economic costs. The etiopathogenesis of PD remains largely unknown, but both genetic and environmental factors contribute to risk. An epigenome-wide association study (EWAS) was conducted to compare medication-free PD patients (n = 89) with healthy controls (n = 76) stratified by gender. Replication was sought in an independent sample (131 cases, 169 controls) and functional analyses were conducted in a third sample (N = 71). DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip. One genome-wide association surviving FDR of 5% (cg07308824, P = 1.094 × 10-7, P-adj = 0.046) was identified in female PD patients (N = 49) compared to controls (N = 48). The same locus, located in an enhancer region of the HECA gene, was also hypermethylated in female PD patients in the replication sample (P = 0.035) and the significance of the association improved in the meta-analysis (P-adj = 0.004). Methylation at this CpG site was associated with HECA mRNA expression in another independent female sample (N = 71) both at baseline (P = 0.046) and after induction by dexamethasone (P = 0.029). Of 15 candidates, 5 previously reported as associated with PD or anxiety traits also showed differences in DNA methylation after gene-wise correction and included SGK1, FHIT, ADCYAP1, HTR1A, HTR2A. Our study examines epigenome-wide differences in peripheral blood for PD patients. Our results point to possible sex-specific methylation changes in the HECA gene for PD but overall highlight that this disorder is not associated with extensive changes in DNA methylation in peripheral blood.


Assuntos
Metilação de DNA , Transtorno de Pânico/genética , Adulto , Ansiolíticos/uso terapêutico , Epigenômica , Feminino , Perfilação da Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/tratamento farmacológico , Transtorno de Pânico/metabolismo
11.
J Psychopharmacol ; 31(6): 715-721, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28583050

RESUMO

The dorsomedial hypothalamus (DMH) and the dorsal periaqueductal gray (DPAG) have been implicated in the genesis and regulation of panic-related defensive behaviors, such as escape. Previous results point to an interaction between serotonergic and opioidergic systems within the DPAG to inhibit escape, involving µ-opioid and 5-HT1A receptors (5-HT1AR). In the present study we explore this interaction in the DMH, using escape elicited by electrical stimulation of this area as a panic attack index. The obtained results show that intra-DMH administration of the non-selective opioid receptor antagonist naloxone (0.5 nmol) prevented the panicolytic-like effect of a local injection of serotonin (20 nmol). Pretreatment with the selective µ-opioid receptor (MOR) antagonist CTOP (1 nmol) blocked the panicolytic-like effect of the 5-HT1AR agonist 8-OHDPAT (8 nmol). Intra-DMH injection of the selective MOR agonist DAMGO (0.3 nmol) also inhibited escape behavior, and a previous injection of the 5-HT1AR antagonist WAY-100635 (0.37 nmol) counteracted this panicolytic-like effect. These results offer the first evidence that serotonergic and opioidergic systems work together within the DMH to inhibit panic-like behavior through an interaction between µ-opioid and 5-HT1A receptors, as previously described in the DPAG.


Assuntos
Hipotálamo/metabolismo , Transtorno de Pânico/metabolismo , Pânico/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Opioides mu/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Analgésicos Opioides/farmacologia , Animais , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Hipotálamo/efeitos dos fármacos , Masculino , Naloxona/farmacologia , Pânico/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Serotonina/farmacologia , Somatostatina/análogos & derivados , Somatostatina/farmacologia
12.
Vitam Horm ; 103: 131-145, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28061968

RESUMO

Natriuretic peptides exert pleiotropic effects on the cardiovascular system, including natriuresis, diuresis, vasodilation, and lusitropy, by signaling through membrane-bound guanylyl cyclases. In addition to their use as diagnostic and prognostic markers for heart failure, accumulating behavioral evidence suggests that these hormones also modulate anxiety symptoms and panic attacks. This review summarizes our current knowledge of the role of natriuretic peptides in animal and human anxiety and highlights some novel aspects from recent clinical studies on this topic.


Assuntos
Transtornos de Ansiedade/metabolismo , Encéfalo/metabolismo , Modelos Neurológicos , Peptídeos Natriuréticos/metabolismo , Neurônios/metabolismo , Sistemas Neurossecretores/metabolismo , Transtorno de Pânico/metabolismo , Animais , Ansiedade/sangue , Ansiedade/metabolismo , Transtornos de Ansiedade/sangue , Encéfalo/irrigação sanguínea , Endotélio Vascular/metabolismo , Medo , Regulação da Expressão Gênica , Humanos , Peptídeos Natriuréticos/sangue , Peptídeos Natriuréticos/genética , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuroproteção , Transtorno de Pânico/sangue , Receptores do Fator Natriurético Atrial/agonistas , Receptores do Fator Natriurético Atrial/genética , Receptores do Fator Natriurético Atrial/metabolismo , Sistemas do Segundo Mensageiro
13.
J Psychopharmacol ; 31(6): 704-714, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28071216

RESUMO

Several studies have shown that serotonin plays a dual role in the modulation of defensive behaviors related to anxiety and panic. A major source of serotonergic projections to limbic structures responsible for this modulation is the dorsal raphe nucleus (DR). Anatomical studies indicate that the prelimbic (PL) cortex sends dense glutamatergic projections to the DR, leading to stimulation or inhibition of serotonin release in structures innervated by the DR. The objective of the present study was to investigate if GABAergic disinhibition of the PL by means of local administration of picrotoxin (PIC), a chloride channel blocker, can affect serotonergic tone and the expression of defensive behaviors related to anxiety and panic. We used the elevated T-maze model and Vogel conflict test to evaluate defensive responses associated with anxiety or panic. The results showed that intra-PL PIC caused an increase in c-Fos activation in serotonergic cells in DR subregions. Furthermore, the intra-PL injection of PIC induced a panicolytic-like effect without affecting behaviors associated with anxiety. Our findings suggest that the PL-DR pathway, through DR serotonergic stimulation, is involved in the control of panic-related behaviors by control of serotonin release in structures that modulate panic responses, such as the dorsal periaqueductal gray.


Assuntos
Transtornos de Ansiedade/metabolismo , Comportamento Animal/fisiologia , Núcleo Dorsal da Rafe/metabolismo , Transtorno de Pânico/metabolismo , Serotonina/metabolismo , Animais , Ansiedade/metabolismo , Núcleo Dorsal da Rafe/efeitos dos fármacos , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Masculino , Pânico/fisiologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Picrotoxina/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/metabolismo
14.
Psychoneuroendocrinology ; 74: 197-202, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27664810

RESUMO

OBJECTIVE: No simple way to augment fear extinction has been established. Cortisol has shown to enhance memory extinction and preliminary evidence suggest that extinction learning maybe more successful in the morning when cortisol is high. The aim was to determine whether exposure sessions conducted earlier in the day are associated with superior therapeutic gains in extinction-based psychotherapy. We also examined the role of cortisol levels as a mediator between time of day and therapeutic gains. METHOD: Participants were 24 individuals meeting DSM-IV criteria for panic disorder with agoraphobia. Participants received 3 weekly in-vivo exposure sessions, yielding 72 total sessions for analysis of time of day effects. Session start times were evenly distributed across the day. The outcome measures were reductions in panic symptom severity (avoidance behaviors, threat misappraisal, perceived control, and panic disorder symptom severity). RESULTS: Sessions starting earlier in the day were associated with superior therapeutic gains by the next therapy session. Earlier sessions were also associated with higher pre-exposure cortisol levels, which in turn were related to greater clinical improvement by the next session. Cortisol thus was found to mediate the effect of time of day on subsequent outcome, providing a link between earlier exposure sessions and greater clinical improvement. CONCLUSION: The data suggest that early-day extinction-based therapy sessions yield better outcomes than later-day sessions, partly due to the enhancing effect of higher cortisol levels.


Assuntos
Agorafobia/metabolismo , Agorafobia/terapia , Extinção Psicológica/fisiologia , Hidrocortisona/fisiologia , Avaliação de Processos e Resultados em Cuidados de Saúde , Transtorno de Pânico/metabolismo , Transtorno de Pânico/terapia , Psicoterapia/métodos , Adulto , Feminino , Humanos , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
15.
Psychiatr Genet ; 26(6): 287-292, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27610895

RESUMO

Panic disorder (PD) is a severe and disabling mental disorder, which is moderately heritable. In a previous study, we carried out a genome-wide association study using patients with PD and control individuals from the isolated population of the Faroe Islands and identified chromosome 19p13.2 as a candidate region. To further investigate this chromosomal region for association with PD, we analysed eight single nucleotide polymorphisms (SNPs) in three candidate genes - small-nuclear RNA activating complex, polypeptide 2 (SNAPC2), mitogen-activated protein kinase kinase 7 (MAP2K7) and leucine-rich repeat containing 8 family, member E (LRRC8E) - these genes have previously been directly or indirectly implicated in other mental disorders. A total of 511 patients with PD and 1029 healthy control individuals from the Faroe Islands, Denmark and Germany were included in the current study. SNPs covering the gene region of SNAPC2, MAP2K7 and LRRC8E were genotyped and tested for association with PD. In the Faroese cohort, rs7788 within SNAPC2 was significantly associated with PD, whereas rs3745383 within LRRC8E was nominally associated. No association was observed between the analysed SNPs and PD in the Danish cohorts. In the German women, we observed a nominal association between rs4804833 within MAP2K7 and PD. We present further evidence that chromosome 19p13.2 may harbour candidate genes that contribute towards the risk of developing PD. Moreover, the implication of the associated genes in other mental disorders may indicate shared genetic susceptibility between mental disorders. We show that associated variants may be sex specific, indicating the importance of carrying out a sex-specific association analysis of PD.


Assuntos
Cromossomos Humanos Par 19/genética , Transtorno de Pânico/genética , Adulto , Cromossomos Humanos Par 19/metabolismo , Estudos de Coortes , Dinamarca , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alemanha , Humanos , MAP Quinase Quinase 7/genética , Masculino , Proteínas de Membrana/genética , Transtorno de Pânico/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
16.
Int J Psychophysiol ; 107: 9-15, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27354161

RESUMO

BACKGROUND: Panic disorder (PD) has been associated with an altered reactivity of the hypothalamic­pituitary­adrenocortical (HPA) system under psychosocial stress. Until now it remains unclear whether a diminished cortisol release is an early risk factor predisposing for PD or a consequence of PD. In order to unravel this point, the present study compares the cortisol secretion between patients with a recent onset and a chronic course of PD. METHODS: The Trier Social Stress Test (TSST) was applied in patients with a duration of PD ≤ 1.5 years (N = 35), patients with a duration of PD > 1.5 years (N = 56) and healthy controls (N = 95). Salivary cortisol and heart rate (HR) were assessed as primary outcomes. RESULTS: According to baseline cortisol/baseline HR and HR response there was no significant difference. Both patient groups (≤ 1.5/> 1.5 years) showed a blunted cortisol response with no significant group difference. In multiple linear regression models the attenuation of the HPA-axis was largely accounted for by group, smoking status, use of contraceptive pill and the interaction group by gender. Female patients with a chronic course showed the lowest cortisol response under the TSST. CONCLUSIONS: It might be assumed that a decreased reactivity of the HPA-axis could be considered as etiological risk factor in the preliminary stages of PD. Above, female gender, smoking status and the use of contraceptive pill seem to further moderate the attenuated HPA-axis response pattern in patients with PD.


Assuntos
Hidrocortisona/metabolismo , Transtorno de Pânico/complicações , Transtorno de Pânico/metabolismo , Saliva/metabolismo , Estresse Psicológico/etiologia , Adulto , Análise de Variância , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
17.
Sci Rep ; 6: 25131, 2016 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-27121911

RESUMO

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice's respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders.


Assuntos
Canais Iônicos Sensíveis a Ácido/genética , Ansiedade de Separação/metabolismo , Código das Histonas , Transtorno de Pânico/metabolismo , Transdução de Sinais , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Ansiedade de Separação/genética , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Interação Gene-Ambiente , Masculino , Bulbo/metabolismo , Camundongos , Transtorno de Pânico/genética , RNA Mensageiro , Análise de Sequência de DNA , Serina-Treonina Quinases TOR/metabolismo
18.
Neuropsychopharmacology ; 41(1): 320-34, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26294108

RESUMO

Fear conditioning has been commonly used as a model of emotional learning in animals and, with the introduction of functional neuroimaging techniques, has proven useful in establishing the neurocircuitry of emotional learning in humans. Studies of fear acquisition suggest that regions such as amygdala, insula, anterior cingulate cortex, and hippocampus play an important role in acquisition of fear, whereas studies of fear extinction suggest that the amygdala is also crucial for safety learning. Extinction retention testing points to the ventromedial prefrontal cortex as an essential region in the recall of the safety trace, and explicit learning of fear and safety associations recruits additional cortical and subcortical regions. Importantly, many of these findings have implications in our understanding of the pathophysiology of psychiatric disease. Recent studies using clinical populations have lent insight into the changes in regional activity in specific disorders, and treatment studies have shown how pharmaceutical and other therapeutic interventions modulate brain activation during emotional learning. Finally, research investigating individual differences in neurotransmitter receptor genotypes has highlighted the contribution of these systems in fear-associated learning.


Assuntos
Aprendizagem por Associação/fisiologia , Encéfalo/metabolismo , Medo/fisiologia , Rede Nervosa/metabolismo , Neuroimagem/métodos , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Animais , Encéfalo/patologia , Mapeamento Encefálico/métodos , Extinção Psicológica/fisiologia , Medo/psicologia , Giro do Cíngulo/metabolismo , Giro do Cíngulo/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Rede Nervosa/patologia , Transtorno de Pânico/metabolismo , Transtorno de Pânico/patologia , Transtorno de Pânico/psicologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia
19.
J Anxiety Disord ; 37: 54-63, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26625098

RESUMO

BACKGROUND: This study examined autonomic responses (salivary alpha-amylase, sAA; heart rate, HR) to repeated psychosocial stress as a candidate mechanism linking autonomic hyper-arousal and sensitization to the occurrence of panic disorder (PD). METHODS: Thirty-three patients with PD and 34 healthy controls were exposed to the Trier Social Stress Test (TSST) twice on consecutive days. RESULTS: sAA changes were comparable between PD and controls on both testing days with overall decreasing sAA responses (delta) on day two. In contrast, HR delta increased on day two in both groups. This sensitization was driven by female controls while male PD showed most pronounced HR changes to the first TSST. CONCLUSIONS: Overall, a general autonomic hyper-arousal in PD could not be confirmed. In contrast, sAA responses slightly habituated to repeated stress. Whether sAA findings mirror assumed habituation effects of repeated stress exposure on normalizing autonomic reactivity remains to be investigated in longitudinal studies.


Assuntos
Transtorno de Pânico/psicologia , Saliva/enzimologia , alfa-Amilases Salivares/metabolismo , Estresse Psicológico/psicologia , Adolescente , Adulto , Análise de Variância , Nível de Alerta/fisiologia , Sistema Nervoso Autônomo/fisiologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Frequência Cardíaca/fisiologia , Humanos , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/metabolismo , Estresse Psicológico/metabolismo , Adulto Jovem
20.
Eur Neuropsychopharmacol ; 26(1): 15-22, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26628106

RESUMO

2-arachidonoylglycerol (2-AG) is an endogenous ligand of the cannabinoid CB1 receptor. This endocannabinoid and its hydrolyzing enzyme, monoacylglycerol lipase (MAGL), are present in encephalic regions related to psychiatric disorders, including the midbrain dorsolateral periaqueductal grey (dlPAG). The dlPAG is implicated in panic disorder and its stimulation results in defensive responses proposed as a model of panic attacks. The present work verified if facilitation of 2-AG signalling in the dlPAG counteracts panic-like responses induced by local chemical stimulation. Intra-dlPAG injection of 2-AG prevented panic-like response induced by the excitatory amino acid N-methyl-d-aspartate (NMDA). This effect was mimicked by the 2-AG hydrolysis inhibitor (MAGL preferring inhibitor) URB602. The anti-aversive effect of URB602 was reversed by the CB1 receptor antagonist, AM251. Additionally, a combination of sub-effective doses of 2-AG and URB602 also prevented NMDA-induced panic-like response. Finally, immunofluorescence assay showed a significant increase in c-Fos positive cells in the dlPAG after local administration of NMDA. This response was also prevented by URB602. These data support the hypothesis that 2-AG participates in anti-aversive mechanisms in the dlPAG and reinforce the proposal that facilitation of endocannabinoid signalling could be a putative target for developing additional treatments against panic and other anxiety-related disorders.


Assuntos
Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Transtorno de Pânico/tratamento farmacológico , Transtorno de Pânico/metabolismo , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Animais , Compostos de Bifenilo/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Imunofluorescência , Masculino , N-Metilaspartato , Transtorno de Pânico/patologia , Substância Cinzenta Periaquedutal/patologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo
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