Behavioural and Neurochemical Consequences of MDMA Self-Administration in Rats

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.