Florey Department of Neuroscience and Mental Health - Theses
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ItemTowards a biobehavioral understanding of methamphetamine use disorder: Investigating psychiatric, cognitive, and genetic factors( 2021)Methamphetamine use is a major health concern globally, with ever-expanding market and an increasing number of users worldwide. In Australia, the number of people with methamphetamine use disorder has increased over the past 10 years, specifically amongst adolescents and young adults. This is a particular concern, as the age of onset of substance use predicts the severity of substance use disorder later in life. In addition, young people are more resistant to treatment. While it is still poorly understood why methamphetamine dependence is increasing in adolescents, literature suggests that methamphetamine use is associated with other psychiatric disorders, deficits in cognition, and certain genes involved in the neurocircuitry of addiction. Therefore, the aim of this thesis was to explore psychiatric, cognitive, and genetic factors associated with early onset of methamphetamine use to gain a holistic understanding of methamphetamine use disorder. To investigate these factors, I conducted a cross-sectional two-group study, recruiting people with a current diagnosis of stimulant use disorder, methamphetamine-type, and controls with no history of substance use disorder. All participants were administered a clinical interview to collect demographic and drug use characteristics. Psychiatric comorbidities and psychotic symptoms were also assessed. Following the interview, participants completed a cognitive task battery assessing attention, speed of processing, cognitive flexibility, working memory, and inhibitory control. Inhibitory control was also assessed using a cue reactivity task that I specifically developed for this project. It consisted of the pseudorandomized presentation of methamphetamine-related cues counterbalanced with control, food-related cues. Upon completion of the study session, whole blood was collected for single nucleotide polymorphism analysis in genes of interest. Genes were selected based on robust preclinical data and results from the meta-analysis presented in this thesis. Poor inhibitory control was identified as an age-dependent risk factor in this thesis, with an earlier age of onset associated with greater deficits. In addition, poor inhibition was associated with an increase in craving upon exposure to methamphetamine-related cues. This is critical as cue-induced craving may lead to relapse after abstinence, and therefore poor treatment outcome. Results from this thesis therefore suggest that pre-existing reduced inhibitory control in adolescence is a risk factor for developing methamphetamine use disorder when methamphetamine is first taken early in life, potentially by perpetuating methamphetamine use and inducing repeated relapses. This thesis also identified comorbid antisocial personality disorder as a strong predictor for age of onset of methamphetamine use. This highlights the need to treat cooccurring mental disorders in young people who use drugs to prevent them from transitioning into problematic use. Lastly, a mutation in the neuregulin-1 gene was associated with early onset methamphetamine use, suggesting that people carrying the gene variant are more likely to develop methamphetamine use disorder when exposed to methamphetamine earlier in life. Taken together, this thesis identified a range of psychiatric, cognitive, and genetic factors associated with early onset methamphetamine use. Findings from this work will contribute to the development of larger studies and clinical trials investigating new early interventions to prevent young people who casually use methamphetamine transitioning into a formal methamphetamine use disorder, thus alleviating the rising burden of disease
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ItemEarly life stress and the extinction of conditioned fear in the developing rat( 2021)Early life stress is a known antecedent to anxiety- and fear-related disorders. It may disrupt the ability to regulate fear and act to trigger the development of an anxiety- or fear-related disorder. Hence, in this thesis, I examined the link between early life stress and fear regulation across development. To do this, I used Pavlovian fear extinction as a model of fear regulation to assess the effects of infancy and peri-adolescent stress in rats. In Chapter 2, I examined whether a chronic infancy stressor altered fear extinction in juvenile rats. This series of experiments utilized the limited bedding and nesting model of chronic infancy stress. I found that chronic infancy stress resulted in the precocious emergence of relapse-prone fear in male juvenile rats. However, chronic infancy stress had little effect on extinction behavior in female juvenile rats, as they exhibited relapse-prone fear regardless of stress condition. In Chapter 3, I investigated whether chronic peri-adolescent stress altered fear extinction in adolescence and adulthood. This series of experiments utilized social isolation as a model of chronic peri-adolescent stress. Peri-adolescent stress had a sex-specific effect on fear extinction. In males, peri-adolescent stress resulted in impairments in extinction recall in adolescent and adult male rats. However, in females, peri-adolescent stress had no effect on fear extinction behavior. In Chapter 4, I explored the interplay between peri-adolescent stress and physical activity on fear extinction in adolescence. Peri-adolescent stress, as modelled by social isolation, impaired extinction recall in male adolescents, but this effect was prevented by increased physical activity. Extinction recall in female adolescents was again unaffected by peri-adolescent stress. Surprisingly, increased physical activity was disruptive to extinction recall in peri-adolescent stressed females. Pharmacological suppression of cellular proliferation in peri-adolescent stressed adolescents blocked the effect of physical activity on extinction recall in both sexes. This suggests that peri-adolescent born cells mediate the interplay between peri-adolescent stress and physical activity effects on extinction behavior. Together, these findings highlight sex-specific outcomes of peri-adolescent stress and physical activity on adolescent brain and behavior. In the final Chapter, I propose the Variable Speed Stress model to interpret the effects of stress in infancy and peri-adolescence. Further, I outline potential reasons for the sex effects and possible avenues for future research. Overall, the findings in this thesis contribute to our understanding of how early life stress affects fear extinction throughout development. It suggests that after early life adversity, stress-induced changes to extinction learning development in males may contribute to a reduction in treatment efficacy for exposure-based anxiety disorder therapies.
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ItemAge related dopamine 1 and dopamine 2 receptor expression in addiction-related behaviours( 2020)Methamphetamine (meth) is a significant social and public health concern worldwide, and a growing problem in Australia. One factor contributing to meth use disorder is the lasting memory of its rewarding experience, which can lead to persistent use in vulnerable individuals. Epidemiological data show that adolescence is a period of heightened vulnerability for developing meth use disorder. Furthermore, sex differences exist in numerous aspects of meth use motivations, behaviours, and consequences. Despite this, few studies have investigated age and sex effects of meth on brain and behaviour. A unified neural mechanism by which substances of abuse, including meth, produce their addictive properties is by increasing dopaminergic transmission throughout the mesocorticolimbic dopamine system. Although dopamine binds to and activates several subclasses of receptor in brain regions implicated in reward processing, the dopamine receptors 1 (D1) and 2 (D2) have been reported to be particularly important for drug-affected behaviour. Importantly, levels of D1 and D2 have been shown to fluctuate throughout development. D1 and D2 signalling may therefore be important mediators of adolescent vulnerability to substance use. However, there are numerous inconsistencies in the literature that describe developmental changes in D1 and D2 expression. Systematic characterisation of these changes is therefore critical for a full understanding of how changes to the dopamine system may affect susceptibility to meth (and other substance) use disorder. As such, the first aim of my thesis was to investigate the postnatal developmental trajectory of D1 and D2 in addiction-related brain regions. This was achieved using D1- and D2-green fluorescent protein (GFP) transgenic mice, starting from the juvenile period through to adulthood. The results showed region-specific changes in D1 and D2 expression occur across development, with the insular cortex (insula) showing the most dramatic changes. In particular, the density of D1 compared to D2 expressing neurons (D1:D2 ratio) in the insula substantially increased from adolescence to adulthood in males. Since substance use disorders are male dominant disorders which often have an adolescent onset, this reduced D1:D2 ratio may be relevant in understanding the neurobiological basis of substance use disorders. The second aim of my thesis was to investigate the role of insula D1 and D2 in potential age and sex differences in meth conditioned place preference (CPP) and aversion (CPA). Although no age or sex differences were observed in CPP to 0.1 or 3 mg/kg meth at a group level, analysis of individual data revealed females were less likely to form a place aversion compared to males, and adolescents formed more of a place preference to 0.1 mg/kg meth compared to adults. Conditioning with 3 mg/kg meth led to age differences in insula D1:D2 ratio in males, reduced age differences in insula D1:D2 ratio in females, and increased the activation of insula D2 expressing cells in adults compared to adolescents. Insula activity and expression of D1 and D2 did not correlate with place preference behaviour. Taken together, these findings suggest distinct sex differences in D1 and D2 expression across development in addiction-related cortical and striatal brain regions may underly age- and sex-associated vulnerability to meth-related behaviours.