James Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
Brain Res Bull. 2013 Feb;91:52-7. doi: 10.1016/j.brainresbull.2013.01.003. Epub 2013 Jan 12.
Recent studies have demonstrated that a preconditioning regimen (i.e., repeated low doses) of MDMA provides protection against the reductions in tissue concentrations of 5-HT and 5-HT transporter (SERT) density and/or expression produced by a subsequent binge regimen of MDMA. In the present study, the effects of preconditioning and binge treatment regimens of MDMA on SERT function were assessed by synaptosomal 5-HT uptake. Synaptosomal 5-HT uptake was reduced by 72% 7 days following the binge regimen (10 mg/kg, i.p. every 2 h for a total of 4 injections). In rats exposed to the preconditioning regimen of MDMA (daily treatment with 10 mg/kg for 4 days), the reduction in synaptosomal 5-HT uptake induced by a subsequent binge regimen was significantly less. Treatment with the preconditioning regimen alone resulted in a transient 46% reduction in 5-HT uptake that was evident 1 day, but not 7 days, following the last injection of MDMA. Furthermore, the preconditioning regimen of MDMA did not alter tissue concentrations of 5-HT, whereas the binge regimen of MDMA resulted in a long-term reduction of 40% of tissue 5-HT concentrations. The distribution of SERT immunoreactivity (ir) in membrane and endosomal fractions of the hippocampus also was evaluated following the preconditioning regimen of MDMA. There was no significant difference in the relative distribution of SERTir between these two compartments in control and preconditioned rats. The results demonstrate that SERT function is transiently reduced in response to a preconditioning regimen of MDMA, while long-term reductions in SERT function occur in response to a binge regimen of MDMA. Moreover, a preconditioning regimen of MDMA provides protection against the long-term reductions in SERT function evoked by a subsequent binge regimen of the drug. It is tempting to speculate that the neuroprotective effect of MDMA preconditioning results from a transient down-regulation in SERT function.
最近的研究表明，重复给予低剂量的 MDMA 预处理方案可防止随后大剂量 MDMA 给药方案引起的 5-HT 组织浓度和（或）5-HT 转运体（SERT）密度和表达降低。在本研究中，通过突触体摄取 5-HT 评估了 MDMA 预处理和 binge 治疗方案对 SERT 功能的影响。在 binge 给药方案（10 mg/kg，每 2 h 腹腔注射 1 次，共 4 次）后 7 天，突触体摄取 5-HT 减少了 72%。在接受 MDMA 预处理方案（连续 4 天每天给予 10 mg/kg）的大鼠中，随后 binge 给药方案引起的突触体摄取 5-HT 减少明显较少。单独给予预处理方案导致 5-HT 摄取的一过性 46%减少，这种减少在最后一次给予 MDMA 后 1 天明显，但在 7 天不明显。此外，MDMA 的预处理方案并未改变 5-HT 的组织浓度，而 MDMA 的 binge 给药方案导致组织 5-HT 浓度长期减少 40%。还评估了 MDMA 预处理方案后海马体膜和内体部分的 SERT 免疫反应性（ir）分布。在对照和预处理大鼠中，这两个隔室之间 SERTir 的相对分布没有显著差异。结果表明，SERT 功能在对 MDMA 预处理方案的反应中短暂降低，而 SERT 功能的长期降低则在对 MDMA 的 binge 给药方案的反应中发生。此外，MDMA 的预处理方案可防止随后大剂量 MDMA 给药方案引起的 SERT 功能长期降低。人们不禁推测，MDMA 预处理的神经保护作用源自 SERT 功能的短暂下调。
