Belcher Annabelle M, O'Dell Steven J, Marshall John F
1Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.
Neuropsychopharmacology. 2005 Nov;30(11):2026-34. doi: 10.1038/sj.npp.1300771.
Repeated moderate doses of methamphetamine (mAMPH) damage forebrain monoaminergic terminals and nonmonoaminergic cells in somatosensory cortex, and impair performance in a novelty preference task of object recognition (OR). This study aimed to determine whether the memory deficit seen after a neurotoxic mAMPH regimen results from damage to dopamine (DA) and/or serotonin (5-HT) terminals. Animals were given a neurotoxic regimen of mAMPH, p-chloroamphetamine (PCA, preferentially damages 5-HT terminals), d-amphetamine (d-AMPH, preferentially damages DA terminals), or saline. After 1 week, animals were trained and tested for OR memory. Rats treated with mAMPH showed no recognition memory during the short-term memory (STM) test, whereas both PCA- and d-AMPH-treated rats showed OR STM scores comparable to controls. After behavioral testing, the specificity of monoaminergic lesions was determined by postmortem [125I]RTI-55 binding to dopamine (DAT) and serotonin (SERT) transporter proteins. Tissue from a separate group of animals killed 3 days after drug treatment was processed for Fluoro-Jade (F-J) fluorescence histochemistry to detect damaged cortical neurons. mAMPH-treated rats showed reductions in striatal DAT and hippocampal (HC) and perirhinal (pRh) SERT, as well as degeneration of neurons in primary somatosensory cortex. In PCA-treated rats, HC and pRh SERT were substantially depleted, but striatal DAT and cortical neuron survival were unaffected. By contrast, d-AMPH-treated animals showed marked depletions in striatal DAT and cortical neurodegeneration, but HC and pRh SERT were unaffected. This pattern of results indicates that no single feature of mAMPH-induced neurotoxicity is sufficient to produce the OR impairments seen after mAMPH treatment.
反复给予中等剂量的甲基苯丙胺（mAMPH）会损害前脑单胺能终末以及体感皮层中的非单胺能细胞，并损害物体识别（OR）新奇偏好任务中的表现。本研究旨在确定在经历神经毒性mAMPH给药方案后出现的记忆缺陷是否源于多巴胺（DA）和/或5-羟色胺（5-HT）终末的损伤。给动物施用mAMPH、对氯苯丙胺（PCA，优先损害5-HT终末）、右旋苯丙胺（d-AMPH，优先损害DA终末）或生理盐水的神经毒性给药方案。1周后，对动物进行OR记忆的训练和测试。接受mAMPH治疗的大鼠在短期记忆（STM）测试中未表现出识别记忆，而接受PCA和d-AMPH治疗的大鼠的OR STM得分与对照组相当。行为测试后，通过死后用[125I]RTI-55与多巴胺（DAT）和5-羟色胺（SERT）转运蛋白结合来确定单胺能损伤的特异性。对药物治疗3天后处死的另一组动物的组织进行氟玉红（F-J）荧光组织化学处理，以检测受损的皮层神经元。接受mAMPH治疗的大鼠纹状体DAT、海马（HC）和嗅周（pRh）SERT减少，以及初级体感皮层中的神经元变性。在接受PCA治疗的大鼠中，HC和pRh SERT大量减少，但纹状体DAT和皮层神经元存活未受影响。相比之下，接受d-AMPH治疗的动物纹状体DAT明显减少且皮层神经变性，但HC和pRh SERT未受影响。这种结果模式表明，mAMPH诱导的神经毒性的单一特征不足以产生mAMPH治疗后出现的OR损伤。
