Há estudos que mostraram que o ácido N-metil-D-aspártico (NMDA), microinjetado nas estruturas do teto mesencefálico (corpos quadrigêmeos) de ratos evoca comportamentos defensivos do tipo pânico que podem ser seguidos por uma resposta antinociceptiva. Tem sido sugerido que respostas defensivas relacionadas ao medo organizadas por neurônios do tronco cerebral podem ser moduladas por projeções ascendentes mediadas pelo neurotransmissor 5-hidroxitriptamina (5-HT) do núcleo dorsal da rafe (NDR), e fenômenos antinociceptivos induzidos pelo medo inato podem ser organizados por vias serotoninérgicas descendentes também originadas no NDR. Os neurônios do NDR que originam tais conexões, por sua vez, podem ser moduladas por monoaminas que recrutam receptores 5-HT2A localizados no NDR. Não obstante, háuma escassez de estudos mostrando o papel dos receptores 5-HT2A do NDR na modulação do comportamento do tipo pânico e da antinocicepção induzida pelo medo inato organizados nos colículos superiores e inferiores. O objetivo deste estudo foi investigar a participação dos receptores 5-HT2A do NDR na modulação do comportamento de defesa organizado pelos corpos quadrigêmeos e da antinocicepção induzida pelo medo evocados por microinjeções de NMDA nos corpos quadrigêmeos. No experimento I, os animais receberam microinjeção de veículo (NaCl 0,9% / 0,2?L) ou 6, 9 e 12 nmol NMDA no CI. No experimento II, foi realizado o pré-tratamento do NDR com microinjeções de veículo ou o antagonista seletivo do receptor 5HT2A (R-96544) nas concentrações de 5, 10 e 15 nM. Dez minutos depois, o NMDA na dose mais efetiva (12 nmol) foi injetado no CI. Em ambos os experimentos, as respostas defensivas foram analisadas quantitativamente durante 10 min e, em seguida, as latências de retirada de cauda foram medidas a intervalos de 10 min durante 70 min. No experimento III, os animais receberam microinjeção de salina fisiológica ou NMDA (6, 9 e 12 nmol) nas cpSC. No experimento IV, a dose mais efetiva de NMDA (12 nmol) ou veículo foi precedida por microinjeções de veículo ou antagonista seletivo do receptor 5HT2A (R- 96544) em diferentes concentrações, 0.5, 5 e 10 nM. Ambos os efeitos pró-eversivos e antinociceptivos provocados pelas injecções intra-cpCS de NMDA foram atenuados pelo pré-tratamento do NDR com R-96544. No experimento V, a análise morfológica mostrou que os receptores 5-HT2A estão presentes nos interneurônios GABAérgicos do NDR. Em conjunto, esses achados sugerem que o bloqueio dos receptores 5-HT2A no NDR é capaz de atenuar tanto o comportamento defensivo do tipo pânico quanto a antinocicepção induzida pelo medo organizada pelos corpos quadrigêmeos. / There are studies that suggest that N-methyl-D-aspartic acid (NMDA) microinjected into the midbrain tectum structures, such corpora quadrigemina, of rats evokes panic-like defensive behaviours that can be followed by an antinociceptive response. It has been suggested that fear-related defensive responses organised by brainstem neurons can be modulated by ascending projections mediated by the neurotransmitter 5-hydroxytryptamine (5-HT) of the dorsal raphe nucleus (DRN), and phenomena of innate fear-induced antinociception can be organised by descending serotonergic pathways also originating from the DRN. The DRN neurons that give rise to such connections, in turn, can be moduled by monoamines that recruit 5-HT2A receptors located in the DRN. Nevertheless, there is a shortage of studies showing the role of DRN 5-HT2A receptors in the modulation of panic-like behaviour and innate fearinduced antinociception organised by superior and inferior colliculi. The purpose of this study was to investigate the participation of DRN 5-HT2A receptors in the modulation of panic-like behaviour and antinociception evoked by corpora quadrigemina injections of NMDA. In experiment I, the animals received microinjection of vehicle (0.9%NaCl/0.2?L) or 6, 9 and 12 nmol NMDA into the IC. In experiment II, it was performed the pretreatment of DRN with microinjections of vehicle or the 5HT2A receptor selective antagonist (R-96544) in a concentration of 5, 10 and 15 nM. Ten minutes later, NMDA at the most effective dose (12nmol) was injected in the IC. In both experiments, the defensive responses were quantitatively analysed for 10 min and then the tail-flick withdrawal latencies were measured at 10 min-intervals for 70 min. In experiment III, the animals received microinjection of physiological saline or NMDA (6, 9 and 12 nmol) into the deep layers of SC (dlSC). In experiment IV, the most effective dose of NMDA (12 nmol) or vehicle was preceded by microinjections of vehicle or 5HT2A receptor selective antagonist (R-96544) at different concentrations (0.5, 5, and 10 nM). Both proaversive and antinociceptive effects elicited by intra-dlSC injections of NMDA were attenuated by the pretreatment of the DRN with R-96544. In experiment V, the morphological analysis showed that 5-HT2A receptors are present in GABAergic interneurons in the DRN. Taken together, these findings suggest that the blockade of DRN 5-HT2A receptors decreased both panic attack-like defensive behaviour and fear- induced antinociception organised by the corpora quadrigemina neurons.

The impacts of exogenous cannabinoids, such as the chemical constituents of Cannabis sativa like cannabidiol (CBD), on brain regions having a modest number of cannabinoid receptors, for example, the ventromedial hypothalamus, are not yet surely knew. A few researches have shown evidence that ventromedial hypothalamus (VMH) neurons play a role in modulating innate fear-induced behavioural reactions in rodents submitted to experimental models of panic attack, for example those based on prey versus wild snake confrontation paradigm. The panic attack-like state was also potentially induced in laboratory animals by N-Methyl-D-aspartate (NMDA), an excitatory amino acid, which stimulates neurons that organize defensive behavioural reactions in the central nervous system. Despite the fact that CB1 receptor-mediated endocannabinoid signaling mechanism underlies the antiaversive effect of exogenous anandamide in medial hypothalamus, there is still a lack of morphological evidence to support the distribution of CB1 receptors in the VMH. Henceforth, this study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and, subsequently, the implication of these receptors in the endocannabinoidmodulated defensive behavioural responses followed by fear-induced antinociception evoked by NMDA microinjected in the VMH. A stainless steel guide-cannula was embedded in the rodent\'s brain coordinated towards VMH by means of stareotaxic surgery. Three different doses of cannabidiol (CBD) were microinjected in the VMH. The most effective dose was used after the pretreatment with the CB1 receptor-antagonist AM251, followed by NMDA microinjection in the VMH. The outcomes demonstrated that the defensive behavioural responses evoked in response to intra-VMH administration of NMDA (6 nmol) were decreased by 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. In addition, the fear-induced antinociception elicited by VMH chemical stimulation diminished after the VMH treatment with CBD, an effect reversed by the intra-diencephalic pretreatment with AM251. These findings suggested that CBD causes panicolytic-like effects when administered in the VMH, and that antiaversive effect recruits the CB1 receptor-endocannabinoid signaling mechanism in VMH. / O papel dos canabinoides exógenos nas regiões do cérebro com um número modesto de receptores cannabinoides, por exemplo, o hipotálamo ventromedial, ainda não está plenamente esclarecido. Algumas pesquisas de nosso grupo, não obstante, mostraram o hipotálamo ventromedial (HVM) exerce modulação de reações comportamentais provocadas pelo medo inato em animais submetidos a um modelo de ataques de pânico. Crises de pânico foram induzidas em animais de laboratório por N-metil-D-aspartato (NMDA), um aminoácido excitatório que, ao ser microinjetado em estruturas do sistema encefálico de aversão, estimula reações comportamentais defensivas no sistema nervoso central que mimetizam as respostas defensivas eliciadas por roedores confrontados com serpentes. Apesar do mecanismo de sinalização endocanabinoide mediado pelos receptores CB1 desempenhar um papel na modulação da neurotransmissão excitadora e inibitória no SNC, ainda há escassez de evidências morfológicas que embasem a distribuição dos receptores CB1 no HVM. Por conseguinte, este estudo foi idealizado para explorar a forma específica de distribuição dos receptores CB1 no HVM e, posteriormente, estudar a implicação desses receptores na modulação de respostas comportamentais defensivas, seguidas por antinocicepção induzida pelo medo, moduladas por endocanabinoides e evocadas por microinjetação de NMDA no HVM. Uma cânula-guia feita de aço inoxidável foi implantada no cérebro do roedor, e direcionada para o HVM por meio de cirurgia estareotóxica. Três diferentes doses de cannabidiol (CBD) foram microinjetadas no HVM. A dosagem mais eficaz foi utilizada após o pré-tratamento do hipotálamo medial com um antagonista do receptor CB1, o AM251, seguido da microinjeção NMDA no HVM. Os resultados demonstraram que as respostascomportamentais defensivas evocadas em resposta à administração intra-HVM de NMDA (6 nmol) foram diminuídas por microinjeções intra-hipotalâmicas de CBD na dose mais alta (100 nmol). Estes efeitos, no entanto, foram atenuados pela administração do antagonista do receptor CB1, AM251, na dose de 100 pmol no HVM. Além disso, a antinocicepção induzida pelo medo foi atenuada pela administração intra-diencefálica de CBA, o que foi revertido pelo pré-tratamenot do HVM com AM251. Esses dados sugerem que o CBD causa efeitos panicolíticos, quando administrado no HVM, envolvendo o mecanismo de sinalização do receptor CB1-endocannabinoide.

Text in Afrikaans / In this study the researcher explored and described the use of Gestalt play therapy with specific focus on self-support with the child in middle childhood years. A literature study was undertaken to examine the concepts of child, Gestalt play therapy, self-support and the play therapy process. This literature study forms the theoretical frame in which this study was done. After the completion of the literature study, the empirical study was conducted. The researcher made use of unstructured interviews within a intrinsic single case study in order to compile research data. During the empirical study ten therapy sessions were conducted with the participant which was explored within the framework of qualitative research methodology. The researcher was able to use ample Gestalt play therapy concepts and principles during the description of the case study in order to explore self-support within the child during middle childhood. These concepts and principles will be discussed in depth within this study. / Social Work / M.Diac. (Spelterapie-rigting)

Background. Previous research suggests that individuals experiencing DSM-IV panic attacks (PA) are at increased risk for various forms of psychopathology, including anxiety, depressive and substance use disorders. However, little is known regarding whether the sole occurrence of fearful spells (FS-only; distressing spells of anxiety with less than four panic symptoms and/or lacking crescendo in symptom onset) similarly elevates the risk for subsequent psychopathology and could therefore be promising to identify high-risk groups for targeted preventive interventions. Thus, the current dissertation thesis aims to examine (a) whether FS-only predict incident mental disorders in addition to full-blown PA and whether their associations with subsequent psychopathology differ from those obtained for PA, (b) whether FS-only, PA, and panic disorder (PD) share similar etiologies, (c) which characteristics of initial FS/PA and other risk factors predict a progression to more severe panic pathology and other mental disorders, and (d) whether help-seeking/potential treatment in individuals with panic alters the risk for subsequent psychopathology. Methods. A representative community sample of adolescents and young adults (N=3021, aged 14-24 at baseline) was prospectively followed up in up to three assessment waves over a time period of up to 10 years. FS-only, PA, PD, and other mental disorders were assessed at each assessment wave using the DSM-IV-M-CIDI. Additional modules/questionnaires were used to assess characteristics of initial FS/PA (T1/T2), potential risk factors, and help-seeking/potential treatment. Logistic regressions were applied to test associations (Odds Ratios, OR) of FS-only and PA at baseline with incident mental disorders at follow-up as well as respective interactive effects with help-seeking at baseline. Associations (Hazard Ratios, HR) of putative risk factors with the onset of panic pathology (FS-only, PA, and PD) or the onset of subsequent anxiety/depressive vs. substance use disorders in those with panic pathology (aggregated data across assessment waves) were estimated with Cox regressions. Multinomial logistic regressions were used to test associations of initial FS/PA characteristics (aggregated from T1 and T2) with PA and PD (lifetime incidences aggregated across assessment waves). Results. FS-only at baseline predicted incident anxiety and depressive disorders at follow-up (OR 1.59-4.36), while PA at baseline predicted incident anxiety, depressive, and substance use disorders at follow-up (OR 2.08-8.75; reference group: No FS/PA). Merely any anxiety disorder (OR=3.26) and alcohol abuse/dependence (OR=2.26) were significantly more strongly associated with PA than with FS-only. Female sex, parental anxiety disorders, parental depressive disorders, behavioral inhibition, harm avoidance, lower coping efficacy, and parental rejection predicted FS-only, PA, and PD (HR 1.2-3.0), whereas the associations with other risk factors partially differed for FS-only, PA, and PD and tended to be more pronounced for PA and PD than for FS-only. Alcohol consumption, use of drugs/medication, and physical illness as perceived reasons for the initial FS/PA were associated with the occurrence of full-blown PA (without PD, OR 2.46-5.44), while feelings of anxiety/depression and having always been anxious/nervous as perceived reasons for the initial FS/PA, appraising the initial FS/PA as terrible and long-term irritating/burdensome, subsequent feelings of depression, avoidance of situations/places, and consumption of medication, alcohol, or drugs were associated with the development of PD (OR 2.64-4.15). A longer duration until “feeling okay again” was associated with both PA and PD (OR 1.29-1.63 per category). Moreover, partially different risk constellations in subjects with panic pathology (FS/PA/PD) predicted the onset of subsequent anxiety/depressive vs. substance use disorders. Panic pathology (FS/PA) and help-seeking/potential treatment at baseline interacted on predicting incident PD (OR=0.09) and depression (OR=0.22) at follow-up in a way that panic pathology only predicted these disorders in individuals not seeking help at baseline. Conclusions. Findings suggest that individuals with FS-only are at similar risk of developing subsequent psychopathology compared to individuals with full-blown PA. Specific initial FS/PA characteristics and additional risk factors may be used to identify sub-groups of individuals with panic pathology, which are at particular risk of progressing to more severe panic pathology or other mental disorders and might therefore profit from supplemental outcome-related preventive interventions in addition to panic-specific treatment. Future research may replicate the current findings and test the efficacy of targeted preventive interventions in panickers at elevated risk for PD and other forms of psychopathology.:CONTENT 0 Synopsis 10 1 Introduction 13 1.1 Current challenges in clinical psychology 13 1.2 Psychological models of mental disorders 13 1.3 Diagnostic approaches to psychopathology 15 1.4 Methodological issues 16 1.5 Preventive and early treatment interventions 17 2 Panic pathology 18 2.1 Definitions 18 2.2 Epidemiology 19 2.3 Etiology 20 2.4 Physiological, neurobiological, and genetic findings 21 2.5 Unresolved issues 22 3 Aims 24 4 Methods 26 5 Study I: Associations of fearful spells and panic attacks with incident anxiety, depressive, and substance use disorders: A 10-year prospective-longitudinal community study of adolescents and young adults 27 5.1 Abstract 27 5.2 Introduction 27 5.3 Materials and methods 28 5.4 Results 30 5.5 Discussion 35 6 Study II: Characteristics of initial fearful spells and their associations with DSM-IV panic attacks and panic disorder in adolescents and young adults from the community 37 6.1 Abstract 37 6.2 Introduction 37 6.3 Materials and methods 38 6.4 Results 41 6.5 Discussion 43 7 Study III: Risk factors for fearful spells and panic: A 10-year prospective-longitudinal study among adolescents and young adults 47 7.1 Abstract 47 7.2 Introduction 47 7.3 Materials and methods 49 7.4 Results 52 7.5 Discussion 60 8 Study IV: Does help-seeking alter the risk for incident psychopathology in adolescents and young adults with and without fearful spells or panic attacks? Findings from a 10-year prospective-longitudinal community study 63 8.1 Abstract 63 8.2 Introduction 63 8.3 Materials and methods 64 8.4 Results 66 8.5 Discussion 70 9 General discussion 73 9.1 Summary and discussion of main findings 73 9.2 Preventive interventions among individuals with panic pathology 75 9.3 Research implications 77 10 Conclusions 78 11 References 79 12 Appendix 94 12.1 Acknowledgements 94 12.2 Erklärung zu den Eigenanteilen an einzelnen Publikationen 95 12.3 Eigenständigkeitserklärung 96 / Theoretischer Hintergrund. Auf Grundlage früherer Forschungsbefunde ist anzunehmen, dass Personen mit DSM-IV-Panikattacken (PA) ein erhöhtes Risiko für zahlreiche psychische Störungen, einschließlich Angst-, depressiver und Substanzstörungen, aufweisen. Unklar ist jedoch, ob das alleinige Auftreten von Fearful Spells (FS-only, Angstanfälle mit weniger als vier Paniksymptomen und/oder fehlendem Crescendo in der Symptomentwicklung) das Risiko für Psychopathologie in ähnlicher Weise erhöht und hilfreich sein könnte, um Hochrisikogruppen für Präventivinterventionen zu identifizieren. Innerhalb der vorliegenden Dissertation wird daher untersucht, (a) ob FS-only zusätzlich zu PA inzidente psychische Störungen vorhersagen und ob sich Unterschiede in den Assoziationen von FS-only vs. PA mit nachfolgender Psychopathologie ergeben, (b) ob FS-only, PA und Panikstörung (PS) ähnliche Ätiologien teilen, (c) welche Merkmale initialer FS/PA und welche anderen Risikofaktoren die Entwicklung schwerer Panikpathologie und weiterer psychischer Störungen vorhersagen und (d) ob Hilfesuchverhalten/potenzielle Behandlung bei Personen mit Panik das Risiko für nachfolgende Psychopathologie verändert. Methodik. Eine repräsentative Bevölkerungsstichprobe Jugendlicher und junger Erwachsener (N=3021, 14-24 Jahre zur Baseline-Erhebung) wurde in bis zu drei Erhebungswellen über einen Zeitraum von bis zu 10 Jahren untersucht. FS-only, PA, PS und andere psychische Störungen wurden zu jeder Erhebungswelle mithilfe des DSM-IV-M-CIDI erfasst. Merkmale initialer FS/PA (T1/T2), mögliche Risikofaktoren sowie Hilfesuchverhalten/potenzielle Behandlung wurden mit weiteren Modulen und Fragebögen erhoben. Mithilfe logistischer Regressionen wurden Assoziationen (Odds Ratios, OR) von FS-only und PA zu Baseline mit inzidenten psychischen Störungen zum Follow-Up sowie diesbezügliche Interaktionen mit Hilfesuchverhalten zu Baseline getestet. Zusammenhänge zwischen möglichen Risikofaktoren und dem Auftreten von Panikpathologie (FS-only, PA und PS) bzw. nachfolgender Angst-/depressiver und Substanzstörungen bei Personen mit Panikpathologie (Verwendung von über die Erhebungswellen hinweg aggregierter Daten) wurden mithilfe von Cox-Regressionen geschätzt. Multinomiale logistische Regressionen wurden genutzt, um Assoziationen von Merkmalen initialer FS/PA (aggregiert über T1 und T2) mit PA und PS (über die Erhebungswellen hinweg aggregierte Lebenszeitinzidenzen) zu erfassen. Ergebnisse. FS-only zu Baseline sagten inzidente Angst- und depressive Störungen zum Follow-Up vorher (OR 1.59-4.36), wohingegen PA zu Baseline inzidente Angst-, depressive und Substanzstörungen zum Follow-Up vorhersagten (OR 2.08-8.75; Referenzkategorie: Keine FS/PA). Lediglich irgendeine Angststörung (OR=3.26) und Alkoholmissbrauch/-abhängigkeit (OR=2.26) waren signifikant stärker mit PA als mit FS-only assoziiert. Weibliches Geschlecht, elterliche Angst- und depressive Störungen, Verhaltenshemmung, Schadensvermeidung, geringere Coping-Erwartung und elterliche Zurückweisung sagten FS-only, PA und PS vorher (HR 1.2-3.0), während sich teils unterschiedliche Assoziationen anderer Risikofaktoren mit FS-only, PA und PS ergaben, die tendenziell stärker für PA und PS als für FS-only waren. Alkoholkonsum, Drogen-/Medikamentengebrauch und körperliche Erkrankungen als wahrgenommene Gründe für die initiale FS/PA waren mit dem Auftreten vollständiger PA assoziiert (ohne PS; OR 2.46-5.44), während Gefühle von Angst/Depression und die Einschätzung schon immer ängstlich/nervös gewesen zu sein als wahrgenommene Gründe für die initiale FS/PA, die Bewertung der initialen FS/PA als schrecklich und langfristig verunsichernd/belastend, nachfolgende Gefühle von Niedergeschlagenheit, Vermeidung von Situationen/Orten und Konsum von Medikamenten, Alkohol oder Drogen mit der Entwicklung von PS assoziiert waren (OR 2.64-4.15). Eine längere Dauer bis sich die betroffene Person wieder vollständig in Ordnung fühlte war sowohl mit PA als auch mit PS assoziiert (OR 1.29-1.63 pro Kategorie). Weiterhin sagten teils unterschiedliche Risikokonstellationen bei Personen mit Panikpathologie (FS/PA/PS) die nachfolgende Entstehung von Angst-/depressiven und Substanzstörungen vorher. Panikpathologie (FS/PA) und Hilfesuchverhalten/potenzielle Behandlung zu Baseline interagierten bei der Vorhersage von inzidenter PS (OR=0.09) und Depression (OR=0.22) zum Follow-Up; d.h. das Vorhandensein von Panikpathologie sagte diese Störungen nur bei Personen ohne, nicht aber bei Personen mit Hilfesuchverhalten zu Baseline vorher. Schlussfolgerungen. Die vorliegenden Ergebnisse implizieren, dass Personen mit FS-only im Vergleich zu Personen mit vollständigen PA ein ähnliches Risiko für die Entwicklung nachfolgender Psychopathologie aufweisen. Spezifische Merkmale initialer FS/PA und zusätzliche Risikofaktoren könnten zur Identifikation von Sub-Gruppen von Personen mit Panik genutzt werden, die sich durch ein besonderes Risiko für schwergradige Panikpathologie und andere psychische Störungen auszeichnen und demzufolge von Outcome-bezogenen Präventionen (ergänzend zu Panik-spezifischer Intervention) profitieren könnten. Zukünftige Studien sollten die vorliegenden Befunde replizieren und die Effektivität gezielter Präventivinterventionen bei Personen mit erhöhtem Risiko für PS und andere psychische Störungen testen.:CONTENT 0 Synopsis 10 1 Introduction 13 1.1 Current challenges in clinical psychology 13 1.2 Psychological models of mental disorders 13 1.3 Diagnostic approaches to psychopathology 15 1.4 Methodological issues 16 1.5 Preventive and early treatment interventions 17 2 Panic pathology 18 2.1 Definitions 18 2.2 Epidemiology 19 2.3 Etiology 20 2.4 Physiological, neurobiological, and genetic findings 21 2.5 Unresolved issues 22 3 Aims 24 4 Methods 26 5 Study I: Associations of fearful spells and panic attacks with incident anxiety, depressive, and substance use disorders: A 10-year prospective-longitudinal community study of adolescents and young adults 27 5.1 Abstract 27 5.2 Introduction 27 5.3 Materials and methods 28 5.4 Results 30 5.5 Discussion 35 6 Study II: Characteristics of initial fearful spells and their associations with DSM-IV panic attacks and panic disorder in adolescents and young adults from the community 37 6.1 Abstract 37 6.2 Introduction 37 6.3 Materials and methods 38 6.4 Results 41 6.5 Discussion 43 7 Study III: Risk factors for fearful spells and panic: A 10-year prospective-longitudinal study among adolescents and young adults 47 7.1 Abstract 47 7.2 Introduction 47 7.3 Materials and methods 49 7.4 Results 52 7.5 Discussion 60 8 Study IV: Does help-seeking alter the risk for incident psychopathology in adolescents and young adults with and without fearful spells or panic attacks? Findings from a 10-year prospective-longitudinal community study 63 8.1 Abstract 63 8.2 Introduction 63 8.3 Materials and methods 64 8.4 Results 66 8.5 Discussion 70 9 General discussion 73 9.1 Summary and discussion of main findings 73 9.2 Preventive interventions among individuals with panic pathology 75 9.3 Research implications 77 10 Conclusions 78 11 References 79 12 Appendix 94 12.1 Acknowledgements 94 12.2 Erklärung zu den Eigenanteilen an einzelnen Publikationen 95 12.3 Eigenständigkeitserklärung 96