Florey Department of Neuroscience and Mental Health - Theses
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ItemThe role of CRFR1 in addiction and anxiety disorders( 2016)Addiction and anxiety disorders are highly co-morbid, and represent a huge burden on society. The central role of stress-reactivity in the pathogenesis and maintenance of both of these diseases has led to the identification of corticotropin-releasing factor (CRF) signalling as a key factor in these effects. The focus of this thesis was the ventral tegmental area (VTA), as it is a site where reward- and fear- related circuitry converge and can be modulated by CRF. The broad aims of this thesis were to examine the role of VTA CRF receptor 1 (CRFR1) in animal models of reward-seeking and conditioned fear to understand how these systems can become dysregulated in addiction and anxiety disorders. To this end, chapter 3 of this thesis validated a technique for the viral-mediated downregulation of CRFR1 within the VTA, and chapter 4 established a novel model of stress-induced reinstatement of cocaine-seeking in mice. These techniques were then implemented to examine the effects of VTA CRFR1 knockdown on the acquisition, extinction, and reinstatement behaviours. Chapters 5 and 6 are two separate publications demonstrating that VTA CRFR1 signalling is differentially involved in various components of cocaine-seeking and conditioned fear. In chapter 5, knockdown of CRFR1 in the VTA blocked stress-induced reinstatement of cocaine-seeking and attenuated cued cocaine-seeking, without any effects on self-administration or extinction responding. This was a specific effect on drug-related behaviours, as there were no changes to operant responding for sucrose rewards. In chapter 6, VTA CRFR1 knockdown enhanced the expression of conditioned fear, but had no effects on fear extinction or reinstatement. This evidence suggests that CRFR1 participates in distinct subcircuits within the VTA which mediate fear and reward-seeking.