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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ItemThe role of the metabotropic glutamate 5 and adenosine 2A receptors in methamphetamine addiction( 2015)Methamphetamine (METH) is a highly addictive psychostimulant for which there are no pharmacotherapies. Current theories of drug addiction suggest a dysregulation of dopamine and glutamate systems in the development and maintenance of addition. Two receptors which modulate dopamine and glutamate transmission, and which have been implicated in animal models of drug-taking behaviour for other drugs of abuse (e.g. alcohol, cocaine, opiates) are the metabotropic glutamate 5 (mGlu5) and the adenosine 2A (A2A) receptors. This project used germline KO mice to identify the role of these receptors in METH-induced behaviour, and determine a neural locus where these receptors might act to mediate this behaviour. Germline deletion of mGlu5 resulted in a deficit in extinction learning for METH in an operant self-administration paradigm, and an increased propensity to reinstate to drug-associated cues. mGlu5 KO mice also demonstrated enhanced locomotor activity when re-exposed to a drug- associated context compared to wildtype (WT) littermates, suggesting mGlu5 may modulate the contextual salience of drug-associated cues and contexts. In contrast, A2A KO mice exhibited abolished conditioned place preference (CPP) and a reduction in the motivation to self- administer METH under high response requirements. There was also a reduction in sucrose self-administration under higher reinforcement schedules in A2A KO mice, suggesting this receptor is involved in the rewarding and motivational properties of both METH and sucrose. c-Fos immunohistochemistry was used to determine a locus where A2A could mediate the rewarding properties of METH, as assessed by CPP. Initially, Fos-immunoreactivity (IR) was examined following the expression of METH CPP in A2A WT and KO mice; however, there was a global reduction in Fos-IR throughout the forebrain in A2A KO mice, preventing the identification of a potential locus. A second experiment was conducted in A2AloxP/loxP mice, examining Fos-IR following the expression vs. non-expression of CPP. This experiment identified the nucleus accumbens (NAcc) shell and the infralimbic cortex as regions activated following the expression of METH CPP. From this, it was hypothesised that A2A activity in the NAcc shell might mediate METH reward. This hypothesis was addressed using viral mediated knockdown of A2A. Adeno-associated virus encoding Cre-recombinase (AAV-Cre) or mCherry (a control fluorophore) were microinjected into the rostral medial NAcc shell of A2AloxP/loxP mice. This resulted in a deletion of approximately 20% of A2A in the rostral medial NAcc shell. There was no effect of AAV-Cre mediated deletion on the expression of METH reward or METH-induced locomotor behaviour. Furthermore, there was no correlation between the degree of knockdown and CPP, supporting the conclusion that a ~20% knockdown of A2A in the rostral medial NAcc shell had no effect on METH reward. In summary, the findings of this thesis implicate A2A in reward and motivated behaviour for METH, but also in these behaviours for natural reinforcers such as sucrose. Although neural correlates suggested increased activity in the NAcc shell during the expression of METH reward- context associations, I was unable to confirm the involvement of A2A in this behaviour using region specific receptor knockdown. In contrast, mGlu5 appears involved in cognitive processes associated with recognition of drug-associated stimuli and the extinction of drug-taking behaviour.