MDMA : binge use and functional outcomes in the rat

Rodsiri, Ratchanee (2009) MDMA : binge use and functional outcomes in the rat. PhD thesis, University of Nottingham.

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3,4-Methylenedioxymethamphetamine (MDMA) use has increased dramatically and more intensive patterns of use such as binging have become common. This thesis pays particular attention to the translation of animal data to humans by examining low doses and binge type repeated regimen of MDMA in the rat. The functional effects especially acute and long-term effects on memory have been investigated together with the measurement of changes in 5-HT and dopamine to investigate the possible link of these neurotransmitters and the functional effects of MDMA.

The acute effect of single low doses of MDMA on memory was initially examined and it was shown that MDMA (3 mg/kg) acutely disrupted novel object discrimination when given 30 min before the test. However there was no change in 5-HT and dopamine in the hippocampus, striatum and frontal cortex 150 min after MDMA administration. The combined techniques of radiotelemetry and in vivo microdialysis were used to examine effects of 'binge-type' repeated low dose MDMA administration (3 or 6 mglkg i.p. x 3 every 2 h). Locomotor activity, body temperature and 5-HT release in the hippocampus were simultaneously measured in the same animal during MDMA administration. MDMA (3 x 6 mglkg) increased locomotor activity after each injection. In addition MDMA (3 x 3 mg/kg) produced hypothermia following each injection while MDMA (3 x 6 mg/kg) changed thermoregulation as it decreased body temperature after the first injection and then increased body temperature after the second to a maximum of + 1.3 °C after the third injection. Both 'binge' doses of MDMA however increased extracellular 5-HT in the hippocampus after each injection and there was no correlation between 5-HT release in the hippocampus and changes either in locomotor activity or body temperature.

The long-term effect of repeated administration of low doses of MDMA (3 or 6 mg/kg i.p. x 3 every 2 h) on memory was investigated using novel object discrimination 2 weeks after treatment. To imitate the single housing condition used in radiotelemetry experiments, rats were individually housed during drug treatment. MDMA (3 x 6 mglkg) caused impairment of novel object discrimination but there was no change in 5-HT, dopamine and their metabolites in the hippocampus, striatum and frontal cortex 2 weeks after MDMA treatment suggesting no contribution of either 5-HT or dopamine loss to the MDMA-induced memory impairment.

The effects of housing conditions on MDMA-induced changes in body temperature and subsequent 5-HT neurotoxicity were determined. Group housed rats showed a similar pattern of changes in body temperature to singly housed rats measured by radiotelemetry following MDMA (3 x 6 mg/kg) suggesting no effect of the housing condition on MDMA-induced changes in body temperature. MDMA (3 x 6 mg/kg) given to group housed rats however produced loss of hippocampal 5-HT 2 weeks after treatment indicating that MDMA-induced hyperthermia is not an essential factor for MDMA-induced neurotoxicity.

The influence of tyrosine on MDMA-induced 5-HT neurotoxicity was determined by depletion of brain tyrosine availability by giving a tyrosine-free amino acid mixture (1 glkg twice 1 h apart) to Dark Agouti rats before and after MDMA administration (12.5 mglkg i.p.). A small increase of tyrosine in the hippocampus and striatum occurred in rats treated with MDMA alone. Although the tyrosine-free amino acid mixture decreased tyrosine in the hippocampus and striatum by more than 50% 2 h after administration, this did not protect against MDMA-induced acute hippocampal and striatal 5-HT depletion and long-term 5-HT loss in the hippocampus indicating no effect of tyrosine on MDMA-induced 5-HT neurotoxicity.

Overall the results of the present study provide extensive evidence for acute and long-term memory impairments following single and 'binge-type' repeated low dose MDMA administration and that these effects may translate effectively to human conditions. The memory impairments appeared to have no link with 5-HT and dopamine thus it is important to focus on other factors involved in

the mechanism of MDMA-induced memory impairments.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Fone, K.C.F.
Marsden, C.A.
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Biomedical Sciences
Item ID: 13386
Depositing User: EP, Services
Date Deposited: 12 Jun 2013 12:45
Last Modified: 16 Dec 2017 14:51

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