The effects of the benzodiazepine, midazolam, on extinction and re-extinction of conditioned fear

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Copyright: Hart, Genevra
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Abstract
Extinction of Pavlovian conditioned fear requires activation of the basolateral amygdala (BLA). Concurrent with this activation, effective long-term extinction requires animals to be able to express and actively inhibit their fear across the course of the extinction session. Benzodiazepines, such as midazolam, inhibit such fear expression. This thesis examines the effect of midazolam on initial extinction and extinction following re-conditioning (re-extinction). Rats were subjected to two cycles of conditioning and extinction, or two conditioning episodes, followed by initial extinction. Midazolam was administered across extinction or re-extinction. Chapter One demonstrated that systemic or intra-BLA administration of midazolam impairs initial extinction but spares re-extinction of conditioned fear. Chapter Two demonstrated that the effects of midazolam on re-extinction are not due to reduced contextual specificity of the extinction memory; as such rats show equally robust renewal of fear as rats re-extinguished under vehicle. Chapter Three demonstrated that rats undergoing re-extinction under midazolam fail to use prediction-error mechanisms to regulate the magnitude of inhibition accrued to the re-extinguished stimulus. Chapter Four demonstrated that systemic or intra-amygdala administration of midazolam facilitates re-extinction; animals given midazolam across re-extinction required significantly less time to re-learn to inhibit their fear responses than those given vehicle. These experiments indicate that whereas initial extinction requires activation of the amygdala-based fear system, re-extinction of fear does not. These results are consistent with a retrieval-based explanation of extinction, where the absence of fear produced by the drug across re-extinction serves to reactivate and strengthen the original extinction memory. In addition, this retrieval and strengthening occurs in the absence of prediction error, and occurs across a much shorter time period than that necessary for normal inhibitory learning.
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Author(s)
Hart, Genevra
Supervisor(s)
Westbrook, Frederick
McNally, Gavan
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Publication Year
2012
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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