Florey Department of Neuroscience and Mental Health - Theses
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ItemThe effects of chronic methamphetamine exposure during adolescence on brain and behaviour( 2018)Methamphetamine is a highly addictive psychostimulant that is used world-wide. The age of initial methamphetamine use typically occurs during adolescence, which is a particularly vulnerable period to the development of addiction. Therefore, this thesis aimed to elucidate the effects of methamphetamine during adolescence compared to adulthood on brain and behaviour. My first study examined the effects of either experimenter-injected binge exposure or self-administration of methamphetamine on subsequent fear related behaviours because the cycle of anxiety following methamphetamine use and withdrawal may be different in adolescence, which may contribute towards their methamphetamine use. In the binge model, adolescent and adult rats were injected with high and increasing doses of methamphetamine followed by fear conditioning. Extinction recall was impaired due to methamphetamine in adults but not adolescents. Methamphetamine self-administration did not differ between adults and adolescents, but it caused a deficit in the acquisition of conditioned fear in adults but not adolescents. In summary, prior methamphetamine exposure had effects on fear conditioning and extinction only in adults, but not in adolescents. My second study examined methamphetamine-cue extinction and cue-induced reinstatement following methamphetamine self-administration. While cue extinction reduced cue-induced reinstatement in adults and adolescents, adolescents showed higher cue-induced reinstatement compared to adults following 2 sessions of cue extinction. This chapter further showed that while adolescent and adult rats acquire methamphetamine self-administration similarly when the dose starts at 0.03 or 0.01 mg/kg/infusion, adolescents increase their methamphetamine intake when dose is increased from acquisition. This suggests that adolescents may be more vulnerable to escalate their methamphetamine intake if the dose is increased. My final study investigated the potential neuroadaptations induced by methamphetamine self-administration in adult and adolescent rats. Genome wide transcriptome analysis of the dorsal striatum identified 30 potential candidate genes with significant RNA expression changes due to methamphetamine. Based on ingenuity pathway analysis, 6 genes were followed up for quantitative real-time polymerase chain reaction validation. The most notable finding was that methamphetamine self-administration caused a decrease in solute-carrier family 18 member a1 (slc18a1) in adolescents but not in adults. The changes in the level of protein encoded by this gene, vesicular monoamine transporter 1 (VMAT1), were further validated by western blot. This chapter identifies factors that may explain adolescent vulnerability to addiction, such as their resistance to cue extinction and escalation of intake with dose increase. Age specific changes in gene expression following methamphetamine self-administration have been observed, which may explain the age-differences in methamphetamine-taking and seeking. Ultimately, these discoveries may provide novel ways to treat methamphetamine addiction depending on the age of onset of methamphetamine use.
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ItemPrefrontal dopaminergic mechanisms of adolescent cue extinction learning( 2016)Addiction and anxiety disorders represent the most prevalent mental illnesses in young people worldwide. Unfortunately, adolescents attain poorer outcomes following extinction-based treatment for these disorders compared to adults. Cue extinction learning involves dopamine signaling via the dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) in the medial prefrontal cortex. In particular, the infralimbic cortex, a subregion of the medial prefrontal cortex, has been implicated in extinction learning in both adolescent and adult rodents. The prefrontal dopamine system changes dramatically during adolescence. However, the role of prefrontal dopamine in adolescent cue extinction learning is poorly understood. Therefore, this thesis aimed to elucidate the role of prefrontal dopamine in adolescent cue extinction, using cocaine self-administration and fear conditioning in rats. My first study examined cocaine self-administration and cocaine-associated cue extinction in adolescent versus adult rats. Adolescents displayed a deficit in cocaine-cue extinction learning compared to adults (postnatal day [P]53 and P88 on cue extinction day, respectively). A single infusion of the full D2R agonist quinpirole into the infralimbic cortex prior to extinction enhanced adolescent cue extinction to reduce relapse-like behavior the next day. This effect was recapitulated by a systemic injection of the partial D2R agonist aripiprazole, an FDA-approved drug for the treatment of psychosis with strong translational potential. My second study examined fear conditioning and extinction in adolescent and adult rats. I first aimed to optimize behavior in late adolescent (P53) and adult (P88) rats during the dark phase of their 12-hour light-dark cycle, to remain consistent with conditions of the previous chapter. However, this produced unreliable behavioral results. In contrast, adolescent rats (P35) consistently display a deficit in long-term fear extinction compared to adults (P88) during the light phase. Infusion of the D1R agonist SKF-81297 into the infralimbic cortex prior to fear extinction had no effect for either age group. However, infusion of quinpirole into the infralimbic cortex significantly enhanced long-term fear extinction in adolescents, whereas it delayed within-session extinction in adults. Interestingly, an acute systemic injection of aripiprazole improved long-term fear extinction in adults. My final experiments measured prefrontal gene expression for D1R, D2R, and D1R relative to D2R (D1R/D2R ratio) in naïve rats across adolescent development, or following cocaine-cue, or fear extinction. There were no significant differences in prefrontal dopamine receptor gene expression across naïve rats age P35, P53, and P88. Following cocaine-cue extinction, prefrontal D1R gene expression was upregulated in adults but not adolescents. By comparison, following fear conditioning, adolescents showed higher D1R and D1R/D2R ratio gene expression compared to adults. D1R/D2R ratio was modulated in opposite directions following fear extinction learning during adolescence versus adulthood. These findings show that adolescents are impaired in extinction of emotionally salient cues across both appetitive (drug) and aversive (fear) learning domains. Functional and molecular data provide novel evidence for divergent involvement of prefrontal dopamine in cue extinction learning across adolescent development. Results not only extend understandings of extinction learning in general, but represent an exciting step towards finding new therapeutic targets to facilitate exposure-based therapy in the clinic.
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ItemThe effects of an inhaled solvent, toluene, on the maturation of white matter in the adolescent rat( 2014)Chronic inhalant abuse causes a pattern of neurological problems, including visuospatial disturbances, impaired cognition, memory loss and ataxia; the deleterious consequences are particularly great for adolescents, who are also the dominant population of inhalant abusers. These disturbances are thought to be strongly associated with abnormalities of the white matter which are frequently observed in neuroimaging studies of inhalant abusers. Little is understood, however, about the underlying mechanisms of injury that induce these white matter changes at the cellular level, although autopsy studies have provided limited evidence that chronic inhalant abuse produces astrogliosis, myelin loss and induces inflammatory responses mediated by microglia. The primary hypothesis of the current study was that exposure to inhalants during adolescence would produce changes to neuroimaging, which would be characterised by white matter pathology, evidenced by astrogliosis, microglial reactivity and myelin loss, but preservation of axonal integrity, in the white matter of adolescent rats. Secondarily, it was hypothesised that recovery would occur following prolonged abstinence. Adolescent male Wistar rats were exposed to 10,000 ppm inhaled toluene for one hour, three times per week for four weeks, from postnatal day 28 (P28) to P54. Volume and diffusivity properties were measured at baseline (P29), immediately post-toluene (P57) and after four weeks of recovery (P87) within the corpus callosum, anterior commissure and cingulum on magnetic resonance and diffusion tensor images. White matter volume increased with age, with exposure to toluene resulting in a significant decrease in the volume of the corpus callosum body relative to controls at P57 (p< 0.05), but not in other regions of white matter. Age, but not treatment, was associated with a decrease in diffusivity over time. Brain tissues were collected and immunohistologically stained with glial fibrillary acidic protein (GFAP) to assess astrogliosis, ionized calcium binding adaptor molecule 1 (IBA-1) to assess microglia reactivity, myelin basic protein (MBP) to examine myelin expression, and neurofilament 200 (NF-200) to examine axonal integrity. The numbers of astrocytes labelled with GFAP, and microglia labelled with IBA-1, were counted, and the optical absorbance of white matter regions stained for MBP and NF-200 were measured at P29, P43, P57 and P87. The body of the corpus callosum contained decreased microglia and increased optical absorbance of MBP in toluene-exposed tissue without changes in astrocytes or neurofilament, which recovered after four weeks of abstinence. These results suggest that the current model of toluene exposure during adolescence does not cause overt pathology, but rather produces subtle delays in white matter maturation in the body, but not the genu, of the corpus callosum.