PhD, University of Cincinnati, 2006, Medicine : Molecular and Developmental Biology

3,4-Methylenedioxymethamphetamine (MDMA) is a ring substituted amphetamine similar in structure to mescaline. Exposure to MDMA from postnatal days (P)11-20 has been shown to induce deficits in spatial learning and memory as well as in path integration learning when the animals are tested as adults. These learning and memory deficits emerge at P30 and persist until P360. This dosing regimen has been shown to decrease serotonin and alter serotonin signaling in the adult brain; however these effects were independent of the learning and memory deficits observed. Finally, dosing on P11 has been shown to increase corticosterone levels during the stress hyporesponsive period, a time when there are attenuated CORT levels. While these areas appear to be important in elucidating the mechanisms underlying MDMA, it is important to investigate systems that may not have been previously implicated in MDMA pharmacology. Microarray analysis revealed 71 genes with altered expression (66 up-regulated and 5 down-regulated) in the hippocampus of adult animals treated from P11-20 with MDMA. Real-time PCR analysis verified 8 out of the 24 genes selected for verification. The 8 verified genes were examined in the striatum of adult animals, with the gene encoding angiotensinogen (AOGEN) up-regulated approximately 75%. Following examination in the hippocampus and striatum, the 8 verified genes were examined in the hippocampi of P12 and P21 MDMA-exposed animals. In P12 animals, nuclear orphan receptor 1 was up-regulated by ~600% and AOGEN was down regulated by 50%; while AOGEN was up-regulated by 3 fold on P21. One gene was selected for further investigation. CAPON, the gene that showed the highest up-regulation during microarray analysis, was analyzed with common pathway members nNOS, PSD-95, and the NMDA receptor subunit 1 (NR1). While CAPON protein was unchanged, the remaining proteins were increased in the dentate gyrus of adult animals. Together with the protein changes associated with N (open full item for complete abstract)

Committee: Dr. Charles Vorhees (Advisor) Subjects: Biology, Neuroscience