Frederick D L, Ali S F, Slikker W, Gillam M P, Allen R R, Paule M G
Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079-9502, USA.
Neurotoxicol Teratol. 1995 Sep-Oct;17(5):531-43. doi: 10.1016/0892-0362(95)00013-h.
Effects of chronic treatment with the putative serotonergic neurotoxicant MDMA were assessed in rhesus macaques using behavior in an operant test battery (OTB) designed to model aspects of time estimation, short-term memory, motivation, learning, and color and position discrimination. After an initial acute dose-response assessment, escalating doses of MDMA (0.10-20.0 mg/kg, im, twice daily, for 14 consecutive days at each dose) were administered, followed by three additional acute dose-response assessments. In general, tolerance to MDMA's acute effects was evident in all OTB tasks by the second week of repeated exposure to each individual MDMA dose and as doses escalated. Baseline OTB performance after chronic treatment was not significantly altered. Residual behavioral tolerance to MDMA's acute effects, however, was evident in all OTB tasks but was least pronounced in the motivation task. Monkeys were sacrificed (21 months after chronic treatment) and brains were dissected into several regions for neurochemical analyses. Serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were analyzed via HPLC. Although MDMA-treated monkeys tended to have lower 5-HT concentrations in the frontal cortex, chronic MDMA treatment had no significant effects on 5-HT concentrations in any brain area sampled. Hippocampal 5-HIAA concentration, 5-HT uptake sites, and turnover of 5-HT of MDMA-treated monkeys were significantly lower than control values. DA concentrations in the CN of MDMA-treated monkeys were significantly greater than control values. No significant effects on DA concentrations were noted in any other brain area sampled. The absence of significant decreases in 5-HT and the general increase in DA concentrations are dissimilar to neurochemical effects reported after a short course of MDMA treatment at relatively high doses. These data suggest that chronic administration of gradually increasing doses of MDMA results in long-lasting tolerance to the drugs acute effects on the complex brain functions modeled in the OTB. It is uncertain, however, if such tolerance is related to the observed decreases in uptake sites and turnover of 5-HT in the hippocampus of these monkeys.
在恒河猴中，使用旨在模拟时间估计、短期记忆、动机、学习以及颜色和位置辨别等方面的操作性测试组合（OTB）中的行为，评估了假定的血清素能神经毒素3,4－亚甲基二氧甲基苯丙胺（摇头丸）的长期治疗效果。在进行初始急性剂量反应评估后，给予递增剂量的摇头丸（0.10 - 20.0毫克/千克，肌肉注射，每天两次，每个剂量连续14天），随后进行另外三次急性剂量反应评估。总体而言，在重复接触每个摇头丸剂量的第二周以及随着剂量递增，在所有OTB任务中对摇头丸急性效应的耐受性都很明显。长期治疗后的基线OTB表现没有显著改变。然而，对摇头丸急性效应的残余行为耐受性在所有OTB任务中都很明显，但在动机任务中最不明显。猴子在慢性治疗后21个月被处死，大脑被解剖成几个区域进行神经化学分析。通过高效液相色谱法分析血清素（5－羟色胺，5-HT）、5－羟吲哚乙酸（5-HIAA）、多巴胺（DA）、3,4－二羟基苯乙酸（DOPAC）和高香草酸（HVA）。虽然接受摇头丸治疗的猴子额叶皮质中的5-HT浓度往往较低，但长期摇头丸治疗对所采样的任何脑区中的5-HT浓度均无显著影响。接受摇头丸治疗的猴子海马体中的5-HIAA浓度、5-HT摄取位点以及5-HT的周转率均显著低于对照值。接受摇头丸治疗的猴子中脑导水管周围灰质中的DA浓度显著高于对照值。在所采样的任何其他脑区中均未发现对DA浓度有显著影响。5-HT没有显著降低以及DA浓度普遍升高，这与相对高剂量的摇头丸短期治疗后报道的神经化学效应不同。这些数据表明，长期给予逐渐增加剂量的摇头丸会导致对药物对OTB中模拟的复杂脑功能的急性效应产生持久耐受性。然而，尚不确定这种耐受性是否与这些猴子海马体中观察到的摄取位点减少和5-HT周转率降低有关。
