An investigation into the role of noradrenergic receptors in conditioned fear : relevance for posttraumatic stress disorder / Erasmus M.M.

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dc.contributor.author Erasmus, Madeleine Monique en_US
dc.date.accessioned 2012-09-10T16:24:19Z
dc.date.available 2012-09-10T16:24:19Z
dc.date.issued 2011 en_US
dc.identifier.uri http://hdl.handle.net/10394/7334
dc.description Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.
dc.description.abstract Posttraumatic stress disorder is a debilitating anxiety disorder that can develop in the aftermath of a traumatic or life–threatening event involving extreme horror, intense fear or bodily harm. The disorder is typified by a symptom triad consisting of re–experiencing, hyperarousal and avoidance symptoms. Approximately 15–25% of trauma–exposed individuals go on to develop PTSD, depending on the nature and severity of the trauma. Although dysfunctional adaptive responses exist in multiple neurobiological pathways in the disorder, e.g. glutamate, GABA, glucocortocoids and serotonin, the noradrenergic system is particularly prominent and represents an important pharmacological target in attempts at preventing the development of PTSD posttrauma. However, current literature shows opposing and conflicting results regarding the effect of selective noradrenergic agents in memory processing, and the effect of modulation of selective noradrenergic receptors are spread over diverse protocols and paradigms of learning and fear also employing different strains of animals. Fear conditioning is a behavioural paradigm that uses associative learning to study the neural mechanisms underlying learning, memory and fear. It is useful in investigating the underpinnings of disorders associated with maladaptive fear responses. Performing fear conditioning experiments with the aim of applying it to an animal model of PTSD, and relating these behavioural responses to a defined neural mechanism, will assist both in the elucidation of the underlying pathology of the disease, as well as the development of more effective treatment. This project has set about to re–examine the diverse and complex role of noradrenergic receptors in the conditioned fear response with relevance to PTSD. To the best of my knowledge, this study represents the first attempt at studying a range of noradrenergic compounds with diverse actions and their ability to modify conditioned fear in a single animal model. This work thus introduces greater consistency and comparative relevance not currently available in the literature, and will also provide much needed pre–clinical evidence in support of treatment strategies targeting the noradrenergic system in the prevention of PTSD posttrauma. The first objective of this study was to set up and validate a passive avoidance fear conditioning protocol under our laboratory conditions using the Gemini Avoidance System. The noradrenergic system plays a prominent role in memory consolidation and fear conditioning, while administration of –adrenergic blockers, such as propranolol, have been shown to abolish learning and fear conditioning in both humans and animals. Propranolol has also demonstrated clinical value in preventing the progression of acute traumatic stress syndrome immediately posttrauma to full–blown PTSD. To confer predictive validity to our model, the centrally active –adrenergic antagonist, propranolol, and the non–centrally acting –adrenergic antagonist, nadolol, were administered to Wistar rats after passive avoidance fear conditioning training in the Gemini Avoidance System. Wistar rats were used because of their recognised enhanced sensitivity to stress. Evidence from this pilot study confirmed that propranolol 10 mg/kg significantly inhibits the consolidation of learned fear in rats, whereas nadolol is ineffective. This effectively validated our protocol and the apparatus for further application in this study and also confirmed the importance of a central mechanism of action for –adrenoceptor blockade in the possible application of these drugs in preventing the development of PTSD posttrauma. The second objective of this study was to investigate the role of 1–, 2–, 1–, and 2–receptors in a conditioned fear passive avoidance paradigm. This was done in order to investigate how selective pharmacological modulation of these receptors may modify the conditioned fear response, and whether any of these receptor systems might exert opposing effects in passive fear conditioning. Various centrally active noradrenergic agents were employed over a 3–tiered dose response design, including the 1–antagonist, prazosin, the 2–agonist, guanfacine, the 2–antagonist, yohimbine, the 1–antagonist, betaxolol and the 2–antagonist ICI 118551. The effect of post–exposure administration of these drugs on conditioned fear was compared to that of propranolol 10 mg/kg. Selected doses of betaxolol (10 mg/kg) and ICI 118551 (1 mg/kg) attenuated fear conditioning to an extent comparable to propranolol, as did prazosin (0.1 mg/kg). Yohimbine tended to boster fear learning at all doses tested, albeit not significantly, while guanfacine did not produce any significant effect on memory retention at any of the doses studied. This latter observation was surprising since yohimbine tended to bolster fear conditioning while earlier studies indicate that 2–agonism impairs conditioned fear. Concluding, this study has conferred validity to our passive avoidance model and has provided greater insight into the separate roles of noradrenergic receptors in contextual conditioned fear learning. The study has provided supportive evidence for a key role for both 1– and 2–antagonism, as well as 1–antagonism, in inhibiting fear memory consolidation and hence as viable secondary treatment options to prevent the development of PTSD posttrauma. However, further study is required to delineate the precise role of the 2–receptor in this regard. en_US
dc.publisher North-West University
dc.subject PTSD en_US
dc.subject Contextual fear conditioning en_US
dc.subject Passive avoidance en_US
dc.subject Memory consolidation en_US
dc.subject Learned fear en_US
dc.subject Propranolol en_US
dc.subject Nadolol en_US
dc.subject Betaxolol en_US
dc.subject ICI 118551 en_US
dc.subject Prazosin en_US
dc.subject Yohimbine en_US
dc.subject Guanfacine en_US
dc.subject Kontekstuele vreeskondisionering en_US
dc.subject Passiewe vermyding en_US
dc.subject Konsolidasie van geheue en_US
dc.subject Aangeleerde vrees en_US
dc.subject Betaksolol en_US
dc.subject Prasosien en_US
dc.subject Johimbien en_US
dc.subject Guanfasien en_US
dc.title An investigation into the role of noradrenergic receptors in conditioned fear : relevance for posttraumatic stress disorder / Erasmus M.M. en_US
dc.type Thesis en_US
dc.description.thesistype Masters en_US

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