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Tolerance to the Behavioural and Neurochemical Effects of MDMA Following Repeated Exposure

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thesis
posted on 10.11.2021, 04:30 by Jones, Karen

Rationale: Following repeated +/-3,4- methylenedioxymethamphetamine (MDMA) administration there is tolerance to many behavioural effects and deficits in serotonergic neurotransmission. Objectives: The present studies had three main objectives. 1. To develop a behavioural assay to examine the effects of acute and repeated MDMA exposure. 2. To use this behavioural assay to determine whether functional changes in serotonin (5-HT)2a or 5-HT2c receptors accompany tolerance to the effects of MDMA. 3. To attempt to reverse behavioural tolerance and 5-HT deficits by administering a treatment that has been shown to desensitise the 5-HT1a autoreceptor. Methods: In separate groups of rats the dose effect curves for MDMAproduced hyperactivity were determined (0.0, 1.0, 3.3, 10.0 mg/kg). In additional groups the effect of MDMA pretreatment (4 X 10mg/kg MDMA injections at 2 hour intervals) or saline vehicle on MDMA-produced hyperactivity was assessed. To determine the experimental parameters for MDMA effects in the Emergence Test (ET) separate groups of rats received MDMA (0.0, 3.3 mg/kg) and were either habituated to a hide box for various periods (15, 30, 45mins) or exposed to the test arena 3 times over a period of days (day 1, 5, 9) or injected daily in the home cage with MDMA (0.0, 3.3mg/kg) for 3 days. Emergence latency following injections of MDMA (0.0, 3.3mg/kg), the 5-HT2a /c agonistm-CPP (0.0, 0.3, 0.6 or 1.25 m/kg), the 5-HT releasing stimulant, fenfluramine (0.0, 1.0, 2.0 mg/kg), and the 5-HT2a agonist DOI (0.0, 1.0, 2.0 mg/kg) was measured. The role of 5-HT2c receptors was assessed by determining the effect of the 5-HT2c antagonist, RS102221 (0.0, 0.25, 0.5, 1.0 mg/kg). The effect of MDMA pretreatment on MDMA (0.0, 3.3 mg/kg), m-CPP (1.25 mg/kg), or fenfluramine (2.0mg/kg) induced increases in emergence latency was also assessed. The functional status of the 5-HT1a autoreceptor following MDMA pretreatment was determined by measuring the effect of the 5-HT1a agonist, 8- OHDPAT (0.0, 0.315, 0.0625, 0.125, 0.25, 0.5 mg/kg, SC), on body temperature. The ability of the 5-HT1a antagonist, WAY100635 (0.0, 0.01, 0.1, 1.0mg/kg, SC, 1 X daily for 7 days or by local injection of 0.0 or 500 ng into the dorsal raphe) to reverse the attenuation of MDMA-induced hyperactivity following MDMA pretreatment was examined. Effects of various treatments on tissue levels of 5-HT and 5-HIAA were also measured using HPLC with EC. Results: MDMA produced dose-dependent hyperactivity and tolerance was produced by MDMA pretreatment. MDMA (3.3mg/kg) increased emergence latency following a 30 minute habituation period and this effect was reduced in MDMA-pretreated rats. Fenfluramine and m-CPP but not DOI also increased emergence latency in a dose-dependent manner. RS102221 dose dependently blocked the acute effects of MDMA and m-CPP. Two weeks following MDMA pretreatment rats were tolerant to the effects of MDMA and fenfluramine, but not m-CPP. MDMA pretreatment also produced significant reductions in tissue levels of 5-HT and 5-HIAA. Subcutaneous WAY100635 administration failed to reverse the behavioural and neurochemical deficits produced by MDMA pretreatment but local administration increased MDMA-produced hyperactivity in saline and MDMA pretreated rats and reversed MDMA-produced 5-HT tissue depletions. Conclusion: The Emergence Test is a behavioural assay sensitive to the effects of acute and repeated MDMA exposure. Following MDMA pretreatment behavioural tolerance as measured by the ET is likely to be due to impaired 5-HT release rather than changes in 5-HT2a or 5-HT2c receptor responses. Because partial reversal of tolerance and 5-HT deficits following repeated MDMA administration was achieved through local DRN 5-HT1a antagonist administration the 5-HT1a autoreceptor may prove to be a clinical target for the reversal of MDMA produced deficits.

History

Copyright Date

01/01/2009

Date of Award

01/01/2009

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; Hunt, Maree