Differential role of dose and environment in initiating and intensifying neurotoxicity caused by MDMA in rats.

BACKGROUND: MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. METHODS: Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. RESULTS: Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. CONCLUSION: Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification.

"SURGENT" -- student e-learning for reality: the application of interactive visual images to problem-based learning in undergraduate surgery.

Information technology has the potential to transform surgical education. Combining symbolic, iconic, and enactive teaching modalities to construct an authentic conceptual model potentially can transform a primarily didactic learning experience into an interactive Web-enhanced one. This study sought to assess the introduction of a Web-based module to complement traditional surgical undergraduate curricula. Adopting the clinical case as its fundamental educational approach, an online resource simulating surgical clinical decision making ("SURGENT," http://www.surgent.ie) was developed, which consists of the interpretation of clinical photographs, laboratory data, and X-rays as well as the formulation of a management plan. Evaluation was in both a qualitative and a quantitative fashion. An anonymous postcourse survey (73% response) of 117 final medical students was used to by researchers to evaluate access, process, and outcome criteria. SURGENT was used by 98% of students, with 69% spending more than 30 minutes per session on the program. First-class honors in the final surgical clinical examination improved from 11% to 20% (p = 0.01) as compared with the previous control year. A Web-enhanced interactive surgical module in an undergraduate course can convey successfully information and understanding beyond the textbook. It is intended that SURGENT will supplement textbooks and ward experience, allowing students to develop their clinical decision-making skills.