- Title
- Understanding striatal neuroadaptations in addiction-relapse vulnerability
- Creator
- Quinn, Rikki Kate
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2016
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Addiction is a cyclical disorder associated with rigid, habit like behaviour and a high propensity to relapse into drug seeking. Up to 90% of addicts will relapse during in their treatment, posing a substantial clinical hurdle to recovery. Currently, few pharmacotherapies are available to aid in recovery from drug seeking and prevention of relapse. The lack of effective treatment options is a product of our limited understanding of the persistent neuroadaptations that render individuals vulnerable to addiction and relapse. The striatum is a critical brain region involved in regulation of many facets of addiction-like behaviour, including reinforcement of conditioned stimuli and regulation of habit-like behaviour. Importantly, the striatum can be divided into four functionally heterogenous subregions: the nucleus accumbens shell (NACsh) and core (NACc) and the dorsomedial (DM) and dorsolateral (DL) striatum. A number of studies have identified changes in synaptic plasticity processes in these regions following illicit drug use. However, the molecular mechanisms that contribute to synaptic plasticity are yet to be fully elucidated. This thesis aimed to uncover the role of a number of critical synaptic plasticity associated genes in the development of addiction. Moreover, I aimed to understand the role of miRNA regulation of these genes, and how these changes in molecular substrates may contribute to addiction vulnerability. I first investigated the role of the mTOR complex 1 (mTORC1) in regulation of cocaine taking, withdrawal and reinstatement of drug use. mTORC1 is a serine threonine kinase involved in the translation of several synaptic plasticity proteins, including AMPAR subunits and CAMKIIα, and has been previously implicated in addiction behaviour. I observed that withdrawal from cocaine taking increased mTORC1 activity in the NAC. Moreover, inhibition of mTORC1 using rapamycin decreased the expression of addiction-like behaviour, while reducing markers of mTORC1 activity. Intra-cerebroventricular injection of rapamycin also decreased the motivation to consume cocaine measured using progressive ratio (PR) testing. Furthermore, inhibition of mTORC1 in the NACsh reduced PR responding as well as cue-induced reinstatement of drug seeking. These addiction behaviours were reduced by systemic administration of rapamycin. Critically, decreased expression of indices of mTORC1 activity were evident in the NAC, but not DS. Together these experiments demonstrate a key role for mTORC1 expression in the NAC but not DS in the regulation of addiction-like behaviour. Importantly, it has been shown that mTOR and other synaptic plasticity genes are altered in the striatum of rats that show evidence of addiction vulnerability. However, the mechanisms contributing to these changes are unclear. Thus, the second aim of this thesis was to assess the role of miRNA in the regulation of these critical synaptic plasticity genes. miRNA are short, non-coding RNA molecules that negatively regulate gene expression. I assessed the expression of miRNA in the striatal subregions and their role in regulation of synaptic plasticity genes. Previous evidence suggests that there is a global downregulation of synaptic plasticity genes, including mTOR, Arc and Drd1, in the striatum of addiction-vulnerable animals compared to resilient controls. However, the results of my first study showed that decreased mTORC1 in the NACsh reduced indices of addiction. Critically, this demonstrates a temporal time course for expression of these genes. As such, I developed a novel method of identifying addiction vulnerable animals throughout the course of the addiction cycle. I found that during the drug-taking phase of addiction cycle, cocaine self-administering rats had altered expression of key miRNA, including miR-101b, miR-137, miR-132 and miR-212 in the striatal subregions. However, there were few changes between vulnerability groups. In contrast, there was a significant increase in the expression of these miRNA in the striatal subregions of addiction vulnerable rats compared to resilient controls following cocaine reinstatement. Importantly, miR-212 has been implicated in the regulation of compulsive cocaine use. Moreover, miR-101b has been previously shown to regulate mTOR, and was found in the current thesis to regulate Drd1 expression. These results suggest that miRNA are involved in the regulation of key synaptic plasticity genes involved in control of addiction relevant behaviour. Overall, the results of this thesis demonstrate a critical role for synaptic plasticity genes including mTOR, Arc and Drd1 and their miRNA regulators in the development of addiction. My findings have helped to elucidate the molecular changes in the striatal subregions that may contribute to addiction vulnerability and an increased propensity to relapse in addicted individuals.
- Subject
- mechanistic target of rapamycin (mTOR); rapamycin; nucleus accumbens; GluA1; CAMKIIα; cocaine; striatum; progressive ratio
- Identifier
- http://hdl.handle.net/1959.13/1349956
- Identifier
- uon:30463
- Rights
- Copyright 2016 Rikki Kate Quinn
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 19 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 329 KB | Adobe Acrobat PDF | View Details Download |