Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Educational Leadership

Abstract

Thirty to 45% of patients who suffer a myocardial infarction (MI) develop anxiety disorders and/or depression, and the development of mood and anxiety disorders following MI is a major risk factor for cardiovascular morbidity and mortality. Depressed post-MI patients have an increased risk of fatal arrhythmias, which are often precipitated by emotional stressors. However, the central nervous system mechanisms that contribute to post-MI anxiety and arrhythmia susceptibility are unknown. Therefore, the studies reported in this dissertation were designed to test the hypothesis that alterations in noradrenergic transmission in the forebrain contribute to the development of anxiety disorders and arrhythmia susceptibility after MI. Using a rat coronary artery ligation model of MI, we first assessed MI-induced changes in cytochrome oxidase activity, an index of metabolic activity, in forebrain regions governing behavioral and autonomic responses to stress. We found that activity of the lateral nucleus of the amygdala and the infralimbic (IL) portion of the medial prefrontal cortex (mPFC) was increased in MI rats compared to sham-operated rats. Electrical stimulation of the locus coeruleus (LC), in a pattern mimicking a mild stressor, decreased metabolic activity in the IL mPFC in MI rats, but not in sham-operated controls. LC stimulation also increased ventricular arrhythmias in MI rats. We next assessed beta-adrenergic receptor (beta-AR) density and G protein coupling in the forebrain of MI rats, since activation of amygdala beta-ARs has been implicated in anxiety. We observed reduced beta1-AR binding in regions of the amygdala and in the IL mPFC of MI rats. Beta-AR signaling in the IL mPFC is critical in the suppression of emotional responses to learned fear cues when the cues no longer predict an aversive event. Therefore we determined if fear extinction and recall of extinction were impaired in MI rats. We found that MI rats exhibited greater emotional responses (freezing) to tones previously paired with footshock, and took longer to extinguish these responses compared to sham-operated controls. Together, our results suggest that MI may induce changes in receptor expression in forebrain regions critical for processing emotionally provocative stimuli.

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