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Methamphetamine Self-Administration: Neurochemical Consequences and Behavioural Effects

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thesis
posted on 2021-11-12, 09:47 authored by Carati, Caleb

It has been suggested that methamphetamine (MA) self-administration is dependent on dopaminergic mechanisms, and that exposure to high doses of methamphetamine is toxic to central dopamine (DA) and serotonin (5-HT) neurons. Most studies, however, have utilised a short duration, high dose, experimenter-administered MA exposure regime, which is not representative of exposure that results from MA use in humans. The present studies sought to investigate the effects of self-administered MA on brain monoamine levels following a short and longer withdrawal period, and to determine the role of D1- and D2-like receptors in the maintenance of MA self-administration and in relapse to MA-seeking. The effects of self-administered MA (0.1 mg/kg/infusion) on tissue monoamine levels were determined in rats either 24 hours or seven days following 20 daily six hour sessions. A yoked-control self-administration protocol was employed to determine the effects of response contingency. The effect of pre-treatment with the D1-like receptor antagonist, SCH 23390 (0.0; 0.01; 0.02 mg/kg; subcutaneous [SC]), or the D2-like receptor antagonist, eticlopride (0.0; 0.0125; 0.025; 0.05 mg/kg; intraperitoneal [IP]) on MA self-administration reinforced according to a fixed ratio (FR) 1, and progressive ratio (PR; 0.2 mg/kg MA) schedule was determined. The effect of these pharmacological manipulations on relapse to MA-seeking was also determined. Additionally, the role of DA in drug-seeking was examined by measuring the effect of priming injections of the direct D1 receptor agonist, SKF 81297 (0.0; 1.0; 2.0; 4.0 mg/kg; IP), the direct D2 receptor agonist, quinpirole (0.0; 1.0 mg/kg; IP), or the DA transporter (DAT) inhibitor, GBR 12909 (0.0; 1.0; 10.0 mg/kg; IP), on MA-seeking behaviour. Self-administered MA produced a transient decrease in tissue levels of DA and an increase in DA turnover. This effect was produced at 24 hours, but not seven days following the final self-administration session. Similar effects were produced in yoked rats that received the same, non-contingent exposure to MA. Pre-treatment with SCH 23390, but not eticlopride, produced a significant alteration in the dose-response curve of MA self-administration reinforced on an FR1 schedule, and reduced MA produced BPs on the PR schedule. MA-seeking was produced by MA, cocaine and GBR 12909. SCH 23390 pre-treatment significantly reduced drug-primed MA-seeking, whereas eticlopride had no significant effect. Finally, neither SKF 81297, nor quinpirole significantly increased MA-seeking. These findings suggest that self-administered MA does not produce the extensive neurotoxicity seen following high-dose experimenter-administered treatment regimes. The finding that pre-treatment with a D1-, but not a D2-like receptor antagonist altered the maintenance of MA self-administration suggests that neuroadaptations take place as a function of MA self-administration, rendering this behaviour more reliant on D1-like receptor mechanisms. This idea is further supported by the finding that a D1-, but not a D2-like antagonist reduced drug-primed MA-seeking, and that priming injections with a D2 agonist failed to increase MA-seeking behaviour. These results are in contrast to the literature on self-administration and reinstatement of drug-seeking following self-administration of other drugs of abuse, and suggest that dependence on different drugs may become mediated by different DA receptor mechanisms.

History

Copyright Date

2012-01-01

Date of Award

2012-01-01

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Psychology

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Doctoral

Degree Name

Doctor of Philosophy

Victoria University of Wellington Item Type

Awarded Doctoral Thesis

Language

en_NZ

Victoria University of Wellington School

School of Psychology

Advisors

Schenk, Susan; Harper, David