Expressional Analyses of Rattus norvegicus Striatal Tissue Following Methamphetamine and Benzylpiperazine Exposure
|dc.contributor.author||Johnstone, Alice Christine|
|dc.identifier.citation||Johnstone, A. C. (2011). Expressional Analyses of Rattus norvegicus Striatal Tissue Following Methamphetamine and Benzylpiperazine Exposure (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/1682||en|
|dc.description.abstract||Methamphetamine is an illicit psychoactive stimulant with a high abuse liability. Addiction to methamphetamine creates a significant burden on public services and a considerable cost to society. It is a complex disorder that has serious physiological and psychological consequences. There are several processes that have been theorised to lead to addiction; however, no one theory provides a comprehensive explanation for methamphetamine addiction development and its persistence. A better understanding of the molecular consequences of exposure to methamphetamine could help elucidate the changes associated with the progression to addiction. In addition, the recreational drug benzylpiperazine is of concern as it mimics the subjective effects of methamphetamine, yet little information exists on its mechanism of action, the long term effects or its propensity to create an addiction. Therefore the aim of this thesis was to investigate the molecular consequences of exposure to methamphetamine to elucidate the changes associated with this addictive drug, and determine whether the same molecular consequences were observed with benzylpiperazine. This study utilised a rodent exposure model to monitor the behavioural and neurological effects of drug exposure in previously drug naïve subjects. Two separate acute exposure experiments were performed where the two drugs showed a similar effect on rodent locomotor behaviour (10 mg.kg-1 and 20 mg.kg-1 benzylpiperazine, 1 mg.kg-1 and 2 mg.kg-1 methamphetamine and saline controls). A chronic exposure over ten days was also used where subjects showed behavioural sensitization (20 mg.kg-1 benzylpiperazine, 2 mg.kg-1 methamphetamine and saline controls). To examine the effect that this drug exposure had on neuronal expression, the striatum was removed from each animal after the exposure period to isolate mRNA and protein. The mRNA expression profiles were comprehensively analysed with Affymetrix® Rat Genome 230 2.0 or Illumina® RatRef-12 cDNA microarrays. Subsequently, twenty-six genes were selected for expressional validation with Quantitative PCR. From these results, five proteins were selected for preliminary investigations of their change in abundance, due to drug exposure, using Western blotting. The results showed that exposure to methamphetamine or benzylpiperazine had a significant effect on expression in the striatum. Acute methamphetamine significantly decreased Vip and Tph2, while acute benzylpiperazine showed a significant increase in the abundance of Oprm1, Vamp1 and Oxt. Chronic exposure to methamphetamine increased CamkIIa and Htr3a while decreasing the abundance of Vip. Chronic benzylpiperazine increased Calcr, Ceacam10 and Oprm1. Pathway analyses of the microarray results showed methamphetamine decreased expression of genes associated with neuronal development. The protein abundance of CALCR and DRD2 was decreased by acute methamphetamine, whereas chronic methamphetamine increased OPRM1. Acute benzylpiperazine increased DRD2 and both acute and chronic benzylpiperazine decreased CAMKII. Chronic benzylpiperazine also decreased the abundance of HTR3A. Although similar trends were observed with the two drugs, it is likely that benzylpiperazine acts through different mechanisms to methamphetamine, although further biological replication is required. This study has identified the involvement of candidates from the serotonergic, opioid and glutaminergic neurotransmitter systems in addition to the dopaminergic system. Hence the adaptation of synaptic strength and the dysregulation of neurotransmission are likely to be involved in the development of methamphetamine addiction.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||Expressional Analyses of Rattus norvegicus Striatal Tissue Following Methamphetamine and Benzylpiperazine Exposure|
|thesis.degree.discipline||Department of Pathology, Christchurch|
|thesis.degree.discipline||Department of Pathology, Christchurch||en_NZ|
|thesis.degree.name||Doctor of Philosophy|
|thesis.degree.grantor||University of Otago|
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