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Behavioural and Neurochemical Consequences of MDMA Self-Administration in Rats

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thesis
posted on 2021-11-12, 12:43 authored by Do, Jennifer

Rationale: Over the past few decades, MDMA has been shown to produce persistent detrimental effects. Animal models have been developed to investigate the effects of self-administered drugs on brain and behaviour, but only a limited number of studies have investigated effects of MDMA. Objectives: The present thesis sought to determine the effects of MDMA self-administration on working memory and tissue levels of 5HT in rats. The role of the 5HT₁ₐ autoreceptor in MDMA-produced deficits in tissue levels of 5HT was also evaluated using neurochemical and behavioural assays. Methods: Rats self-administered a total of 165mg/kg MDMA, and were then tested in the Novel Object Recognition (NOR) task 1 week or 9 weeks following the last session of MDMA self-administration. Tissue levels of 5HT were measured in separate groups of rats, following self-administration of a total dose of 165mg/kg or 315mg/kg. 8-OH-DPAT-induced lower lip retraction (LLR) was measured in rats 2 weeks following either self-administered (315mg/kg) or experimenter-administered (40mg/kg) MDMA. In subsequent studies, chronic 8-OH-DPAT (daily injections over 7 days; 1.0mg/kg/day), chronic trazodone (continuous infusion over 14 days via osmotic minipump; 10mg/kg/day) and tryptophan loading (oral administration over 7 days; 125mg/day via gavaging needle) were administered after MDMA treatment (either self-administered; 315mg/kg or experimenter-administered; 40mg/kg) and tissue levels of 5HT were measured. Results: Self-administered MDMA produced deficits in NOR that recovered 10 weeks following self-administration. There was a small decrease in tissue levels of 5HT at both 2 weeks and 10 weeks following the low dose of self-administered MDMA. Two weeks following the high dose, tissue levels of 5HT were decreased by about 30% in all brain regions examined, and there was recovery 10 weeks following exposure. 8-OH-DPAT-induced LLR was unchanged in MDMA-treated rats. Furthermore, none of the treatments restored tissue levels of 5HT following MDMA exposure, even though the treatment (chronic 8-OH-DPAT) shifted the basal 8-OH-DPAT-induced LLR curve to the right, suggesting autoreceptor desensitisation. Conclusions: Self-administered MDMA produced deficits in NOR, which may reflect impaired attention, encoding, novelty seeking or other cognitive processes. Dose- and time-dependent deficits in tissue levels of 5HT were modest compared to those produced by experimenter-administered MDMA. Therefore, MDMA self-administration may be important for pre-clinical investigation of long-term consequences of MDMA. The findings are not consistent with the idea that the 5HT₁ₐ autoreceptor became supersensitive as a result of MDMA exposure, and it is therefore not a viable pharmacological target for restoring tissue levels of 5HT.

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