Jeder Vierte erleidet im Laufe seines Lebens einen Verkehrsunfall. Obwohl psychische Folgen verbreitet und vielfältig sind, bleiben sie oft unbeachtet oder ihnen wird erst Aufmerksamkeit zuteil, wenn wenn das Leiden oder die Beeinträchtigung durch sie zu stark werden oder die Symptomatik sich längst chronifiziert hat. Am Lehrstuhl für Klinische Psychologie und Psychotherapie der TU Dresden wurde in Zusammenarbeit mit der Christoph-Dornier-Stiftung für Klinische Psychologie in Dresden ein Forschungsprojekt zu psychischer Traumatisierung nach Verkehrsunfällen durchgeführt. Schwerpunkt dieser Studie war es, herauszufinden, inwieweit psychische Beeinträchtigungen wenige Tage nach einem Verkehrsunfall sowie 3 und 6 Monate danach auftreten und welche auslösenden bzw. aufrechterhaltenden Faktoren für die psychischen Beeinträchtigungen zu finden sind. Zu diesem Zweck wurden in einer Unfallklinik Patienten mit einer Fragebogenbatterie untersucht, die dort nach einem Verkehrsunfall eingeliefert worden waren. Die Auftretenshäufigkeit von posttraumatischer Belastungssymptomatik steigt über den Untersuchungszeitraum hinweg leicht an, dies gilt sowohl für klinische als auch subklinische Symptomatik. Interessant sind hier v.a. die verschiedenen Verlaufstypen. Die Gedanken-kontrollstrategien "Ablenkung" und "Sorgen" scheinen beim Umgang mit auftretenden Intrusionen eine relevante Rolle im Zusammenhang mit der posttraumatischen Belastungssymptomatik spielen. Weiterhin zeigte sich, daß Variablen wie die subjektiv wahrgenommene Kontrollierbarkeit der Unfallsituation oder die Beschäftigung mit der Frage "Warum gerade ich?" Einfluß auf die Entwicklung posttraumatischer Symptomatik ausüben. Die Ergebnisse der Studie haben mehrere Implikationen: Erstens konnte repliziert werden, daß posttraumatische Belastungssymptomatik nach Verkehrsunfällen ein relevantes Problem ist, das nicht einfach ignoriert werden darf. Zweitens konnten Erkenntnisse über den längsschnittlichen Verlauf der Symptomatik bereitgestellt werden, die eine Früherkennung von potentiellen Betroffenen näher rücken läßt. Drittens und letztens konnte die wichtige Rolle der kognitiven Variablen bei der Entstehung einer Posttraumatischen Belastungsstörung nach Verkehrsunfällen untermauert werden.

This thesis presents an eclectic mix of studies which consider laterality in the context of previous findings of increased prevalence of Posttraumatic Stress Disorder (PTSD) in male combat veterans with non-consistent right hand preference. Two studies extend these findings not just to civilian populations and women, but to left handers and find that left, rather than mixed, handedness is associated with increased prevalence of PTSD in both general population and clinical samples, and to severity of symptoms in the former. To examine issues relevant to the fear response in healthy populations, a movie excerpt is shown to be theoretically likely to target the emotion of fear and to generate subjective and physiological (skin conductance) responses of fear. The film is used as a laboratory analogue of fear to examine possible differences in left and right handers in memory (for events of the film) and in an emotional Stroop paradigm known to produce a robust and large effect specifically in PTSD. According to predictions based on lateralisation of functions in the brain relevant to the fear response, left handers show a pattern of enhanced memory for visual items and poorer memory for verbal material compared to right handers. Immediately after viewing the film, left handers show an interference effect on the Stroop paradigm to general threat and film words and increased response latency compared to right handers, approaching performance of previously reported clinical samples with PTSD. A novel non-word Stroop task fails to show these effects, consistent both with accounts of interference as language processing effects and compromised verbal processing in PTSD. Unexpected inferior performance of females in memory for the film, contrary to previous literature, may also be amenable to explanations invoking compromised left hemisphere language functions in fear situations. In testing one theory of left handedness as due to increased levels of in utero testosterone, the 2D:4D (second to fourth digit ratio) provides mixed evidence in two samples. A possible association of more female-like digit ratios in males with PTSD is a tentative finding possibly relevant to sex differences in prevalence of PTSD. A critique of existing and inadequate theoretical accounts of handedness concludes the thesis and proposes a modification of the birth stress hypothesis to one specifically considering peri-natal trauma to account for the above findings. This hypothesis remains to be empirically tested.

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may result from an exposure to a severely traumatic life-event. It is characterised by a delayed onset of psychological and physical symptoms including re-experiencing the event, avoidance of reminders associated with the trauma, increased autonomic arousal and distinct memory deficits. This disorder is also characterised by a maladaptive hypothalamic-pituitary-adrenal (HPA)-axis response and altered monoamine concentrations in the hippocampus and pre-frontal cortex. The Time Dependent Sensitization (TDS) model is a putative animal model of PTSD that is based on the concept of repeated trauma, using three acute stressors (TS) of intense severity followed by a mild situational reminder (RS) on day 7 subsequent to the acute stressors. The aims of this study were to determine if the Triple Stressor (TS) induces stress and if the situational reminder (RS) is necessary for the maintenance of the stress response over time and whether these two stress responses are qualitatively and quantitively different. This was done to further validate the TDS model and to characterize the development and progression of the stress-related pathology of PTSD. Methods used were High Performance Liquid Chromatography (HPLC) with electrochemical detection (biochemical correlates) for quantifying the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) concentrations in the hippocampus and pre-frontal cortex (PFC); radio immuno assay (RIA) for the determination of plasma corticosterone concentrations (neuroendocrine parameter) and the use of the Elevated Plus Maze (EPM) to detect anxiety-like behaviour (behavioural analyses). The study was subdivided into an Acute and Re-Stress study (n = 10). In the Acute Study rats were exposed to TS as the only stressor. Group 1 was sacrificed immediately after TS, Group 2 was sacrificed 3 days post TS and Group 3 on day 7 post TS. In the Re-Stress Study both TS and RS were used as stressors. Group 4 was sacrificed immediately after the situational reminder, Group 5 was sacrificed 3 days post RS and Group 6 on day 7 post RS. A group of unstressed rats were used as Control. The results of this study found corticosterone concentrations elevated immediately after the TS (p<0.05). Exposure to the RS resulted in a profound hypocortisolism (p<0.05). These results indicate a possible disturbance in the regulation of the HPA-axis, which manifests as an enhanced negative feed-back upon re-introduction of the stressful situation. Changes in MA concentrations were evident. Although no definite fixed trend is apparent in this study, it is evident that the TDS model does induce monoamine dysregulation. Hippocampal NA. DA and 5-HT concentrations were noted to be elevated on day 7 post TS (p<0.05). On day 7 post RS only hippocampal 5HT was decreased significantly (p<0.05). Behavioural analyses indicate that stress related anxiety was not sustained after the TS but 7 days after the exposure to the RS rats were most anxious (p<0.05). The results confirm that the TDS model does induce PTSD-like symptoms in rats and that the situational reminder (RS) is necessary for the maintenance of the stress response. This model may be useful in the investigation of future experimental pharmacological interventions in the management of PTSD. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

La présente thèse porte sur l’évaluation de l’efficacité d’un nouveau traitement pour le trouble de stress post-traumatique (TSPT). Le traitement a été développé selon les prémisses de la théorie de la reconsolidation des souvenirs. Il consiste en six courtes séances de remémoration de l’événement traumatique réalisées sous l’effet du propranolol, un bêtabloquant. La population de l’étude est constituée de patients souffrant d’un TSPT chronique. La thèse comporte cinq chapitres. Le premier chapitre est l’introduction, on y retrouve une description du TSPT, des traitements validés empiriquement, de diverses théories de la mémoire, d’un modèle étiologique du TSPT, d’études sur la consolidation et la reconsolidation, de la pharmacocinétique et du mécanisme d’action du propranolol,ainsi que des objectifs de la thèse. Le second chapitre est une revue critique de littérature sur la théorie de la reconsolidation. Comme l’étude du phénomène de la reconsolidation est récente, nous tentons de faire le point sur l’état des connaissances dans le domaine, dans un effort de réflexion sur la validité de la théorie. Nous proposons une série de critères permettant de différencier la reconsolidation d’autres processus connexes. Nous concluons que la théorie paraît valide, bien que d’autres études soient nécessaires afin de rendre compte de résultats négatifs publiés par le passé. Le troisième chapitre est un essai ouvert, et vise à évaluer l’efficacité d’un traitement basé sur la reconsolidation à diminuer la sévérité et l’incidence du TSPT, auprès de 42 patients souffrant d’un TSPT chronique. Le traitement consiste en six séances de remémoration de l’événement traumatique sous propranolol. Lors d’un suivi à trois mois, nous rapportons une diminution des symptômes de TSPT de 41%-56%, ainsi qu’une diminution de l’incidence du TSPT de 74%. En comparaison, seulement 2/25 patients du groupe contrôle (ayant participé uniquement aux évaluations) ne souffrent plus d’un TSPT. Dans le groupe traitement, les tailles d’effet (d de Cohen)varient entre 1.32-2.19. Le quatrième chapitre a comme objectif d’identifier des caractéristiques des patients prédisant l’efficacité du traitement, et d’explorer s’ils s’améliorent dans des domaines de santé autres que le TSPT. Nous rapportons que les femmes s’améliorent davantage que les hommes, mais que d’autres facteurs, tels que la sévérité des traits de personnalité borderline ou le type de trauma (enfance versus adulte), n’influent pas sur l’efficacité. Également, les patients s’améliorent dans les domaines de santé suivants : la qualité de vie, la symptomatologie dépressive, l’intensité des émotions négatives au rappel de l’événement traumatique et dans la vie courante. Le cinquième chapitre contient la discussion générale de la thèse. Nous effectuons une synthèse et interprétation des résultats, nous examinons les hypothèses alternatives à l’amélioration clinique et abordons des pistes de recherches futures. Nous concluons que le traitement à l’étude a été efficace dans notre échantillon de patients souffrant d’un TSPT chronique. Étant donné la méthodologie employée (essai ouvert), nous ne pouvons statuer sur le mécanisme d’action du traitement, à savoir si l’amélioration clinique a été réellement causée par un blocage de la reconsolidation des souvenirs. / This dissertation aims at exploring the efficacy of a new treatment for posttraumatic stress disorder (PTSD). The treatment was developed in accordance with an emerging theory in neuroscience, the reconsolidation theory, and it consists in six short reactivation sessions of a traumatic memory under the influence of propranolol (a ß-blocker), with patients suffering from longstanding PTSD. This dissertation includes five chapters. Chapter I is the introduction, it includes a discussion on the following topics : definition and prevalence of PTSD,empirically validated treatments in the field, memory theories, etiology of PTSD, studies on consolidation and reconsolidation, pharmacokinetics of propranolol and its mechanism of action in reconsolidation, and the objectives of the dissertation. Chapter II is a critical literature review on reconsolidation theory. We discuss some of the contradicting findings in reconsolidation, as some researchers have reported negative results in the field. We address the possibility to reconcile these discrepancies,within the scope of evaluating the validity of the theory. We also discuss a series of criterion which could provide guidance in differentiating reconsolidation from other processes. We conclude that reconsolidation theory seems valid, although more research is needed in order to shed light on some negative results that were published in the past. Chapter III is an open label trial comprising six sessions of treatment (trauma reactivation under propranolol) with 42 patients suffering from chronic PTSD. At a three-month follow-up, we report that patients have a 41% - 56% reduction in PTSD symptoms, and that 31 / 42 patients no longer meet the diagnostic threshold for PTSD. In comparison, only 2 / 25 patients from the control group (assessments only) don’t meet the diagnostic threshold for PTSD. In the treatment group, effect sizes (Cohen’s d) range between 1.32 -2.19. Chapter IV follows on the previous chapter’s study, and aims at identifying predictors of treatment outcome (i.e., predictors of the improvement in PTSD symptoms), and whether patients also improve in health domains other than PTSD. We report that women improve more than men during the treatment, but that other factors such as borderline personality severity traits or type of trauma (childhood versus adulthood) do not influence treatment outcome. Patients also improve in diverse health domains during the treatment; they have a better quality of life, less depressive symptoms, less intense negative emotions in daily life and during trauma recollection. Chapter V contains a general discussion and a conclusion. We summarize and interpret the results, we explore alternative hypotheses to the clinical improvement as well as future research directions. We conclude that this treatment yielded interesting results in our sample of patients suffering from chronic PTSD. However, our methodology (open label study) doesn’t provide any information on the mechanism of action of the treatment used in this dissertation, i.e. whether the clinical improvement was caused or not by reconsolidation blockade.

Veterans suffering from posttraumatic stress (PTSD), compared to relative trauma-exposed veterans without PTSD, have more serious relationship problems. Research in the area of combat trauma-related symptoms and intimate partner relationships have to-date, mostly focused on identifying the negative outcomes of trauma but have not elaborated on how the symptoms themselves act as agents in negative relationship functioning. The purpose of this study was to identify a relationship between combat-related PTSD symptoms of insomnia/sleep dysfunction, avoidance/emotional numbing, and intimate partner distress - specifically the mechanisms by which symptoms and distress are maintained or exacerbated. A review of combat trauma and relationship theories indicated that a newly applied theory, Conservation of Resources (COR) could account for specific combat trauma symptomology, the effects of non-PTSD intimate partners’ distress, and the course of these aspects. This study predominately utilized quantitative data for exploratory correlational research. One hundred and fifteen Canadian combat veterans completed self-administered questionnaires that included demographic characteristics, supplementary questions and the study variables: PTSD assessment, dyadic adjustment, and sleep issues. Results indicated that PTSD overall is negatively related to dyadic adjustment, and that avoidance symptoms represent the most detrimental cluster of PTSD in terms of relationship functioning. Although insomnia/sleep dysfunction was not correlated to dyadic adjustment for those with PTSD, it was identified as a contributor to negative relationship functioning through supplementary responses. The study suggests a revised Canadian PTSD prevalence rate of 29%, which is noteworthy when compared to the previous PTSD prevalence rate estimation of 10%. The application of COR theory to combat veterans and relationship functioning is supported by the results of this study. Findings of this study can aid clinicians in the enhancement of couple therapies, draw attention to the need for improved deployment screening and care provisions for military members, and contribute to the breadth of empirical literature.

Hintergrund: Sexuelle Dysfunktionen sind ein häufiges Problem bei Patientinnen mit posttraumatischer Belastungsstörung (PTB). Kaum untersucht ist, ob ein Zusammenhang zwischen der Art des Traumas (sexuell vs. nichtsexuell) und der Häufigkeit sexueller Dysfunktionen bzw. Zufriedenheit besteht und welche Rolle komorbide Depressionen dabei spielen. Zudem wurden verschiedene Störungsbilder (PTB, Angst, Depression) in Bezug auf sexuelle Funktions-/Zufriedenheitsbeeinträchtigungen vergleichend untersucht (klinische Spezifität). Patientinnen und Methoden: Nach der standardisierten klinischen Diagnostik wurden 351 ambulante Psychotherapiepatientinnen folgenden 3 Gruppen zugeteilt: Patientinnen mit PTB (n = 89), mit anderen Angststörungen (n = 157) und mit depressiven Störungen (n = 105). Informationen zur sexuellen Zufriedenheit und Funktionsfähigkeit wurden mit dem Kurzfragebogen für Sexualität (KFS) erhoben. Die Art des Traumas (sexuell vs. nichtsexuell) wurde per Interview erfasst; Depressivität mit dem Beck-Depressions-Inventar (BDI). Ergebnisse: Sexuell traumatisierte PTB-Patientinnen haben ein 4-fach höheres Risiko, Beeinträchtigungen der sexuellen Funktionsfähigkeit zu erleben als PTB-Patientinnen mit nichtsexuellem Trauma. Bei Vorliegen einer depressiven Störung zusätzlich zur PTB steigt das Risiko für sexuelle Dysfunktionen um das 3-fache gegenüber PTB-Patientinnen ohne komorbide Depression. Mit der sexuellen Zufriedenheit hängt die Art des Traumas hingegen nicht zusammen. Während drei Viertel der PTB- und Depressionspatientinnen sexuelle Dysfunktionen berichten, gilt dies nur für jede zweite Angstpatientin (außer PTB). Diskussion: Sowohl die Art des Traumas als auch komorbide Depressionen stehen im Zusammenhang mit sexuellen Dysfunktionen bei PTB-Patientinnen. Insbesondere bei Patientengruppen mit einem erhöhten Risiko für Beeinträchtigungen der sexuellen Funktionen ist es wichtig, die Thematik bei therapeutischen Interventionen zu berücksichtigen. / Background: Sexual dysfunctions are a common problem in female patients with posttraumatic stress disorder (PTSD). However, only few studies have investigated the incidence of sexual dysfunctions in PTSD patients accounting for the type of traumatisation (sexual vs non-sexual), the role of co-morbid depression as well as the comparison to other psychiatric disorders (clinical specification). Patients and Methods: In this study, 351 female outpatients were tested with a standardised clinical diagnostic instrument and assigned to the following 3 groups: patients with PTSD (n = 89), with other anxiety disorders (n = 157) and with depressive disorders (n = 105). Information about aspects of sexual satisfaction und sexual functioning was assessed by a short questionnaire (‘Kurzfragebogen für Sexualität’, KFS). The type of trauma was assessed by interview, and the level of depressive symptoms with the Beck Depression Inventory (BDI). Results: The risk of suffering from sexual dysfunctions was 4 times higher for sexually compared to non- sexually traumatised patients, and 3 times higher in the case of co-morbid depression compared to PTSD patients without co-morbid depression. Yet, there was no association between sexual satisfaction and type of trauma. Only half of the patients with anxiety disorder (except PTSD) suffer from sexual dysfunctions compared to 3 out of 4 patients with depression or PTSD. Discussion: Both the type of trauma and co-morbid depression are related to sexual dysfunction in patients with PTSD. Especially with patient groups that hold an increased risk of developing sexual dysfunctions, it is important to consider this topic during therapeutic interventions. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may result from an exposure to a severely traumatic life-event. It is characterised by a delayed onset of psychological and physical symptoms including re-experiencing the event, avoidance of reminders associated with the trauma, increased autonomic arousal and distinct memory deficits. This disorder is also characterised by a maladaptive hypothalamic-pituitary-adrenal (HPA)-axis response and altered monoamine concentrations in the hippocampus and pre-frontal cortex. The Time Dependent Sensitization (TDS) model is a putative animal model of PTSD that is based on the concept of repeated trauma, using three acute stressors (TS) of intense severity followed by a mild situational reminder (RS) on day 7 subsequent to the acute stressors. The aims of this study were to determine if the Triple Stressor (TS) induces stress and if the situational reminder (RS) is necessary for the maintenance of the stress response over time and whether these two stress responses are qualitatively and quantitively different. This was done to further validate the TDS model and to characterize the development and progression of the stress-related pathology of PTSD. Methods used were High Performance Liquid Chromatography (HPLC) with electrochemical detection (biochemical correlates) for quantifying the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) concentrations in the hippocampus and pre-frontal cortex (PFC); radio immuno assay (RIA) for the determination of plasma corticosterone concentrations (neuroendocrine parameter) and the use of the Elevated Plus Maze (EPM) to detect anxiety-like behaviour (behavioural analyses). The study was subdivided into an Acute and Re-Stress study (n = 10). In the Acute Study rats were exposed to TS as the only stressor. Group 1 was sacrificed immediately after TS, Group 2 was sacrificed 3 days post TS and Group 3 on day 7 post TS. In the Re-Stress Study both TS and RS were used as stressors. Group 4 was sacrificed immediately after the situational reminder, Group 5 was sacrificed 3 days post RS and Group 6 on day 7 post RS. A group of unstressed rats were used as Control. The results of this study found corticosterone concentrations elevated immediately after the TS (p<0.05). Exposure to the RS resulted in a profound hypocortisolism (p<0.05). These results indicate a possible disturbance in the regulation of the HPA-axis, which manifests as an enhanced negative feed-back upon re-introduction of the stressful situation. Changes in MA concentrations were evident. Although no definite fixed trend is apparent in this study, it is evident that the TDS model does induce monoamine dysregulation. Hippocampal NA. DA and 5-HT concentrations were noted to be elevated on day 7 post TS (p<0.05). On day 7 post RS only hippocampal 5HT was decreased significantly (p<0.05). Behavioural analyses indicate that stress related anxiety was not sustained after the TS but 7 days after the exposure to the RS rats were most anxious (p<0.05). The results confirm that the TDS model does induce PTSD-like symptoms in rats and that the situational reminder (RS) is necessary for the maintenance of the stress response. This model may be useful in the investigation of future experimental pharmacological interventions in the management of PTSD. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

Posttraumatic stress disorder (PTSD) is classified as an anxiety disorder and the characteristic symptoms (re-experiencing, avoidance as well as numbing of general responsiveness and hyperarousal) of this disorder develop in response to a traumatic event. The disorder is characterised by hypothalamic-pituitary-adrenal (HPA) axis abnormalities linked with changes in cortisol moreover, the hippocampus and cortex also play a role in the neurobiology. With regard to the neurochemistry of this disorder it is known that gamma amino butyric acid (GABA) is involved however, the precise role of GABA in PTSD and how stress changes GABA concentrations in the brain are still not fully understood. Another aspect regarding PTSD that has not been clearly defined is the treatment of PTSD. Classic anxiolytics such as diazepam is expected to relieve the anxiety linked with PTSD. Studies with this group of drugs have however not produced the concrete evidence needed to establish it as a treatment of choice for PTSD and subsequently other classes of drugs have been investigated as possible treatment options for PTSD. Among these is lamotrigine, which in a clinical study was found to be effective in alleviating symptoms of PTSD. Moreover, a possible pharmacokinetic-pharmacodynamic relationship for each of these drugs has also not been elucidated. In order to elude on some of these uncertainties, an animal model of PTSD, time dependent sensitisation (TDS), was used. GABA levels in the rat hippocampus and frontal cortex were determined at two different time intervals following the TDS procedure (1 day and 7 days post re-stress). High performance liquid chromatography (HPLC) with electrochemical (EC) detection was used to determine gamma amino butyric acid (GABA) concentrations. To investigate the possible anxiolytic effects of diazepam and lamotrigine in this model, as well as a possible pharmacokinetic-pharmacodynamic relationship for each drug, pharmacokinetic profiles for both drugs were established in order to find the times of peak and trough levels of each drug. Blood samples were collected at different time intervals after drug administration either from the tail vein of rats (lamotrigine) or directly from the heart (diazepam). Subsequently, drug concentrations at each time interval were determined by means of HPLC with ultraviolet (UV) detection. The behaviour of rats was analysed using the elevated plus-maze (EPM) at peak or trough concentrations of the drugs and this was performed after either acute administration of the drug, or after a 14 day chronic treatment regime. GABA levels in the hippocampus were not found to change statistically significantly in response to stress at either 1 day or 7 days post re-stress. In the frontal cortex, however, GABA levels increased in response to stress at 1 day post re-stress, with a statistically insignificant, but strong trend towards an increase, at 7 days post re-stress. With regard to the pharmacokinetic profiles, the peak concentration of diazepam was found to occur at 60 minutes, with lamotrigine's peak at 120 minutes. The behavioural studies indicated that acute treatment with diazepam 3 mg/kg resulted in a statistically significant increase in both ratio open arm entries and ratio time spent in the open arms at peak level of the drug. After acute treatment with diazepam 3 mg/kg a statistically significant decrease in ratio time spent in open arms was also found when the ratio time spent in open arms at peak level of the drug and the ratio time spent in open arms at trough level of the drug was compared. In response to chronic treatment with diazepam 3 mg/kg for 14 days, test animals exhibited an increase in the ratio open arm entries at trough level of the drug, with a statistically insignificant yet definite trend towards an increase at peak level. Acute treatment with lamotrigine 10 mg/kg resulted in no statistically significant change in EPM parameters. In response to chronic treatment, however, a statistically significant increase was found in ratio time spent in open arms at peak level of the drug, with a statistically insignificant trend towards an increase at trough level. From the results of this study, we may therefore conclude that GABA-levels in the brain are definitely affected, but in different ways, following TDS-stress. A pharmacokinetic-pharmacodynamic relationship between the drugs' levels and aversive behaviour could also be established. Furthermore it appears that more sustained anxiolytic effects are evident following chronic treatment with both drugs than with acute administration of these drugs. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2006

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may follow exposure to severe emotional trauma and presents with various symptoms of anxiety, hyperarousal and cognitive anomalies. Interestingly, only 10-30% of an exposed population will go on to develop full-blown PTSD. Cholinergic neurotransmission is implicated in anxiety as well as other typical manifestations of PTSD, particularly cognitive changes. The frontal cortex and hippocampus regulate and in turn are affected by stress, and have also been implicated in the underlying neuropathology of PTSD. These areas are densely innervated by cholinergic neurons originating from the basal forebrain. In this study, the time dependent sensitization (TDS) model was used to induce symptoms of PTSD in animals. The study was designed to determine the long-term effects of an intense, prolonged aversive procedure on central muscarinic acetylcholine receptor (mAChR) characteristics and the correlation if any of those findings to cognitive aspects and general arousal as characteristics associated with PTSD. In order to achieve this goal, male Sprague-Dawley rats were exposed to the TDS stress paradigm with behavioral/neuro-receptor assessments performed on day 7 post re-stress (duration of each experiment in whole is 14 days). Acoustic startle reflex (ASR) was used to determine emotional state (hyperarousal), while the conditioned taste aversion (CTA) paradigm was implemented in order to assess aversive memory. Muscarinic receptor binding studies were performed in the frontal cortex and hippocampus. Moreover, both the stress-exposed and control animals were pre-tested in the acoustic startle chamber in order to attempt to separate stress sensitive from stress-resilient animals based on predetermined ASR criteria. The ASR niodel was previously validated in our laboratory, while the CTA model was validated in this project before application. In the CTA model, an i.p. injection with lithium chloride (LiCl) (associated with digestive malaise), was used as unconditioned stimulus (US) and was paired with a saccharinlcyclamate drinking solution as conditioned stimulus (CS) to induce aversion to the novel taste (CS) when presented in the absence of the US. Population data of animals tested in the ASR experiment indicated no statistical significant difference between stressed and control animals. However, when each animal was assessed individually, 22.5 % of the exposed population displayed all increase above the predetermined criteria of 35 % in startle response, indicating a state of heightened arousal. In contrast, only 4.2 O h of control animals (no stress) displayed an increase in arousal based on the above mentioned criteria. Muscarinic receptor densities (Bm,) in the total population of animals exposed to stress showed a statistical significant increase in both the hippocampus and frontal cortex when compared to controls, with no changes in & values observed in either one of the areas. In the CTA experiment, TDS stress was implemented as US paired with a saccharinlcyclamate drinking solution as CS. An acute session of prolonged stress (as used in the TDS model) effectively induced aversion to a novel taste and a subsequent reminder of the stress (restress) paired with the CS sustained the acquire adversive memory. Furthermore, LiCl was reintroduced as US in order to assess the effect of prior exposure to two types of stress (acute and TDS) on subsequently acquired CTA memory. Prior exposure to acute stress had no significant effect on subsequently acquired aversive memory when measured either 3- or 7 days post-conditioning (CS-US). Stress-restress (TDS) exposure, however, indicated a significant decrease in aversive memory from 3- to 7 days post-conditioning (CS-US) as well as a significant decrease in aversive memory between the control- and the TDS group 7 days post-conditioning. The mAChR density (B,,) in the frontal cortex; but not in the hippocampus, was elevated at the same point in time (7 days post CS-US pairing) that CTA memory was impaired following TDS stress (stress-restress). Ultimately, these data support an association between altered cholinergic receptors and hyperarousallanxiety in an animal model of PTSD. The data also support the phenomenon of individual susceptibility to stress in animals that parallels that observed in humans exposed to severe trauma. Impaired aversive memory (CTA) is a consequence of prior exposure to TDS stress, but not acute stress, and is likewise mediated by an altered central cholinergic transmission displayed as an increase in mAChRs in the frontal cortex. The lack of studies regarding the influence of the cholinergic system in PTSD related behavior earns ,this project value as inimitable PTSD research. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.