Examination of Phasic and Sustained Fear Responses Using a
Novel Sustained Fear Conditioning Paradigm
By: Leigh Miles
Basic research has greatly improved our understanding of the neural mechanisms underlying emotional disorders such as fear and anxiety. Preclinical research has shown that while fear- and anxiety- like responses share similar physiological symptoms, they are mediated by different neural substrates. The medial division of the central nucleus of the amygdala (CeAM) is necessary for the expression of fear-like responses to short-duration, predictable threats (operationally defined as phasic fear), and the bed nucleus of the stria terminalis (BNST) is necessary for the expression of anxiety-like responses to more long-duration, less predictable threats (operationally defined as sustained fear).
Experiments within this dissertation used fear-potentiated startle procedures to further examine the neural mechanisms mediating phasic and sustained fear responses in rats. Studies were designed to measure within-subject phasic and sustained fear, to pharmacologically dissociate fear responses using treatments that either are or are not clinically effective anxiolytics, and to evaluate if the selective serotonin reuptake inhibitor fluoxetine mediates its effects through serotonin within the BNST.
Rats received a single pre-test injection of the benzodiazepine chlordiazepoxide (10 mg/kg), the 5-HT1A partial agonist buspirone (5 mg/kg), the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg), or chronic (21-day) fluoxetine treatment and were tested for phasic and sustained fear. The role of serotonin within the BNST in chronic fluoxetine treatment was assessed in rats given chronic fluoxetine and then tested for sustained fear 48 hrs after bilateral BNST infusions of the serotonin lesioning agent, 5,7-dihydroxytryptamine (2µg/side).
Acute chlordiazepoxide (clinically effective treatment) blocked sustained but not phasic responses, acute buspirone (not clinically effective) did not affect sustained, but did disrupt phasic responses, chronic fluoxetine (clinically effective treatment) blocked sustained responses and unreliably reduced phasic responses, and acute fluoxetine (not clinically effective) affected neither. The results provide further evidence that phasic and sustained fear are mediated by different neural mechanisms and suggest that sustained fear may have greater predictive validity as a model of clinical anxiety as compared to phasic fear. Finally, although not statistically significant, results suggest that serotonin within the BNST may be important for the anxiolytic effects of chronic fluoxetine in this model.
Table of Contents
Table of Contents
Chapter 1: General introduction...1
Chapter 2: Modification of phasic and sustained fear paradigms...17
Chapter 3: Phasic and sustained fear are pharmacologically dissociable in rats...52
Chapter 4: The role of serotonin (within the bed nucleus of the stria terminalis) in sustained fear...94
Chapter 5: General discussion...132
About this Dissertation
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