Amygdala, anxiety & alpha-1 adrenoreceptors : investigations utilizing a rodent model of traumatic stress /

by Manion, Sean T

Amygdala, Anxiety & !1 Adrenoceptors: Investigations Utilizing a Rodent Model of Traumatic Stress Sean T. Manion Directed by He Li, M.D., Ph.D., Associate Professor Department of Psychiatry and Neuroscience Program, F. Edward Hebert School of Medicine, Center for the Study of Traumatic Stress, Uniformed Services University of the Health Sciences Exposure to traumatic stress can result in post-traumatic stress disorder (PTSD) and other pathophysiological conditions. PTSD is characterized by a number of persistently heightened physiological and behavioral indicators, including exaggerated acoustic startle response (ASR) and alterations in processing of emotional memory. Similar effects can be seen in an animal model of traumatic stress in which stress results from restraint and inescapable tailshocks to rats. The basolateral amygdala (BLA) is an area known to be involved in the processing of emotional memory and startle modulation. Synaptic plasticity in the BLA is thought to play a key part in this memory formation, and therefore can be involved in subsequent stress related pathologies seen in PTSD. The first part of this project used this model of traumatic stress to investigate the effects of prazosin, an !1 adrenergic receptor (AR) antagonist, on stress induced elevation of ASR. Recent studies have shown the effectiveness of prazosin in treating PTSD. This investigation sought to determine its effectiveness in reducing the effects of traumatic stress when given prior to stress. Male Sprague-Dawley rats were injected with 0.5 mg/kg iii of prazosin 30 minutes before inescapable tail shock on three consecutive days. ASR testing was performed 1, 4, 7 and 10 days post-stress and compared to baseline and control values. Results show a significant reduction of ASR hyperarousal in the pre-stress injection group. Pre-stress treatment with lower levels of prazosin (0.25, 0.1 and 0.05 mg/kg) showed similar reduction in ASR hyperarousal due to stress. The second part of this project sought to investigate !1A adrenoceptor involvement in long-term potentiation (LTP) in the BLA and to determine the effects of traumatic stress on this type of plasticity. In the BLA of control animals, the !1A AR specific agonist A61603 (1 "M) completely abolished theta-burst stimulation-induced LTP. In animals previously exposed to a repeated restraint and tailshock stress protocol, only a partial reduction of LTP was detected in the presence of A61603. This blocking effect of A61603 on LTP in control animals was occluded in the presence of !1A AR specific antagonist WB4101 (1 "M), while the antagonist did not eliminate the partial reduction of LTP in stressed animals. These findings suggest a possible mechanism contributing to the emotional memory in PTSD and support that the !1A ARs can be a specific pharmacological target in PTSD. Taken together, these findings offer both the possibility of preventative treatment for certain physiological symptoms of PTSD by administering prazosin prior to stress, as well as the potential involvement of !1A ARs in the BLA in the emotional memory aspects of PTSD. iv Amygdala, Anxiety & !1 Adrenoceptors: Investigations Utilizing a Rodent Model of Traumatic Stress by Sean T. Manion Dissertation submitted to the faculty of the Graduate Program in Neuroscience of the Uniformed Services University of the Health Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2006 v