Impaired object recognition memory following methamphetamine, but not p-chloroamphetamine- or d-amphetamine-induced neurotoxicity
Impaired object recognition memory following methamphetamine, but not p-chloroamphetamine- or d-amphetamine-induced neurotoxicity
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DOI：
10.1038/sj.npp.1300771
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发表时间：
2005-11-01
影响因子：
7.6
通讯作者：
Marshall, JF
中科院分区：
文献类型：
--
作者：
Belcher, AM;O'Dell, SJ;Marshall, JF
反复中等剂量的甲基苯丙胺（mAMPH）会损伤前脑单胺能终端和体感觉皮层的非单胺能细胞，并损害在物体识别（OR）的新奇偏好任务中的表现。本研究旨在确定神经毒性mAMPH治疗后出现的记忆缺陷是否由多巴胺（DA）和/或5-羟色胺（5-HT）终末损伤引起。动物被给予mAMPH、对氯苯丙胺（PCA，优先损害5-HT末端）、d-安非他明（d-AMPH，优先损害DA末端）或生理盐水的神经毒性方案。1周后进行OR记忆训练和测试。经mAMPH处理的大鼠在短期记忆（STM）测试中没有识别记忆，而经PCA和d- amph处理的大鼠的OR STM评分与对照组相当。在行为测试后，通过死后[I-125]RTI-55结合多巴胺（DAT）和血清素（SERT）转运蛋白来确定单胺能病变的特异性。对另一组在药物治疗后3天死亡的动物组织进行荧光组织化学处理，以检测受损的皮质神经元。经mamph处理的大鼠纹状体DAT、海马（HC）和外周血管（pRh） SERT减少，初级体感觉皮层神经元变性。在pca处理的大鼠中，HC和pRh SERT大量减少，但纹状体DAT和皮质神经元存活不受影响。相比之下，d- amph处理的动物显示出层状DAT和皮质神经退行性变的显著减少，但HC和pRh SERT未受影响。这种结果模式表明，没有任何一种mAMPH诱导的神经毒性特征足以产生mAMPH治疗后所见的OR损伤。
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 [I-125]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 stratal 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.