Neuroadaptive Changes in 5-HT1A Autoreceptor Sensitivity Following High-Dose MDMA Treatment [thesis]

Simon David Fisher
<p>Rationale: There is evidence that the serotonin (5-HT) deficits and related cognitive and mood impairments caused by +/-3,4- methylenedioxymethamphetamine (MDMA) may be mediated by neuroadaptations of the 5-HT1A autoreceptor. Objectives: The increase in sensitivity of the 5-HT1A autoreceptor caused by highdose, repeated MDMA treatment was assessed neurochemically, by measuring 5- HTP accumulation, and physiologically, via changes in body temperature. Methods: Experiment 1 confirmed the
more » ... s of 8-hydroxy-2-(di-npropylamino) tetralin (8-OH-DPAT) (0, 0.025, 0.05, 0.1 mg/kg s.c.) on 5- hydroxytryptophan (5-HTP) accumulation following 3-hydroxybenzylhydrazine dihydrochloride (NSD-1015) administration as a valid measure of 5-HT synthesis and hence 5-HT1A autoreceptor sensitivity in rats. Experiment 2 performed these procedures in additional animals, with half receiving MDMA (4x 10 mg/kg i.p. at 2 hour intervals) two weeks before testing. Body temperature changes due to the 8-OH-DPAT hypothermic response were tested using a rectal probe. Experiment 2b repeated the procedures in additional groups with lower doses of 8-OH-DPAT (0.0125 and 0.00625 mg/kg s.c.). Results: No significant changes in 5-HTP accumulation levels or changes in the hypothermic response to 8-OH-DPAT were found between MDMA pretreated rats and controls in Experiments 2 and 2b. Moreover, there was no substantial evidence of expected 5-HT deficits due to high-dose MDMA treatment. Conclusion: The results do not indicate an increase in sensitivity of the 5-HT1A autoreceptor, and hence the original hypothesis is not supported. However, there were a number of methodological issues, as indicated by the lack of MDMAinduced 5-HT deficits, which prevent a firm conclusion from being drawn. Future research is outlined to overcome these issues.</p>
doi:10.26686/wgtn.16985362.v1 fatcat:633zlz27sjhthpdbgdyhkslmcu