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

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. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.

Identiferoai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/7334
Date January 2011
CreatorsErasmus, Madeleine Monique
PublisherNorth-West University
Source SetsSouth African National ETD Portal
Detected LanguageEnglish
TypeThesis

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