Date of Award
Doctor of Philosophy
Dr. Lisa Baker
Dr. Alan Poling
Dr. Jack Michael
Dr. Kjell Svensson
It is well established that repeated, high doses of 3, 4-methylenedioxymethamphetamine (MDMA) result in the long-term depletion of serotonin levels and destruction of serotonergic terminals in various locations in the brains of a variety of species. Further, it is also well known that concomitant injections of the serotonin reuptake inhibitor, fluoxetine, prevents this deterioration. It has recently been noted that such MDMA neurotoxicity disrupts stimulus control in rats trained to discriminate MDMA from saline in a drug discrimination procedure (Schechter, 1991a).
In order to extend Schechter's findings to the optical isomers of MDMA and to explore the potential of fluoxetine for the prevention of the disruption of the isomers' discriminative stimulus control by neurotoxicity, rats were trained to discriminate either (+)-MDMA or (-)-MDMA in a two-lever water reinforced operant procedure. Most of the rats administered (-)-MDMA died during the neurotoxic administration, obviating any conclusions thereof. However, the stimulus control by (+)-MDMA was maintained in rats administered concomitant injections of fluoxetine and the neurotoxic dose of (±)-MDMA, but disrupted in those that received (±)-MDMA with concomitant saline injections. Control by (+)-MDMA was reestablished in these latter rats with subsequent training sessions. Postmortem neurochemical analysis verified the neurotoxic effects of the (±)-MDMA injection regimen in that serotonin and its major metabolite 5-HIAA were significantly diminished in the prefrontal cortices in rats given (+)-MDMA relative to control. Conversely, serotonin levels in rats administered concomtitant (±)-MDMA and fluoxetine injections were unaffected relative to control, indicating pharmacological protection against MDMA neurotoxicity.
The deaths of the (-)-MDMA rats are discussed in light of the predominant environmental variables, and it is suggested that elevated temperatures during (±)- MDMA treatment may have contributed to their mortality. However, the results from the surviving rats indicate that the discriminative stimulus control of (+)-MDMA as disrupted by (±)-MDMA neurotoxicity can be established, regained, and protected against. Although there appears to be a relative paucity in research regarding the behavioral consequences MDMA neurotoxicity, the present findings shed new light on the potential use of fluoxetine as a tool for such explorations.
Virden, Thomas B. III, "Disruption of the Discriminative Stimulus Effects of (+)-3, 4-Methylenedioxymethamphetamine (MDMA) by (± )-MDMA Neurotoxicity: Protection by Fluoxetine" (1998). Dissertations. 1592.