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.