BEHAVIORAL EVIDENCE FOR A MODULATING ROLE OF SIGMA-LIGANDS IN MEMORY PROCESSES .1. ATTENUATION OF DIZOCILPINE (MK-801)-INDUCED AMNESIA
BEHAVIORAL EVIDENCE FOR A MODULATING ROLE OF SIGMA-LIGANDS IN MEMORY PROCESSES .1. ATTENUATION OF DIZOCILPINE (MK-801)-INDUCED AMNESIA
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DOI：
10.1016/0006-8993(94)91397-8
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发表时间：
1994-05-30
期刊：
影响因子：
2.9
通讯作者：
NABESHIMA, T
中科院分区：
文献类型：
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作者：
MAURICE, T;HIRAMATSU, M;NABESHIMA, T
最近报道了小剂量α配体对N-甲基-D-天冬氨酸(NMDA)诱导的锥体细胞CA3背侧神经元兴奋的增强作用。在本研究中，我们在非竞争性NMDA拮抗剂地佐西平(MK-801)诱导的小鼠实验性遗忘症中研究了与这些发现相关的行为效应。Sigma配体1，3-二(2-甲苯基)胍(DTG)、(+)-SKF 10,047和(+)-五唑碱(但不包括它们的(-)-)异构体，在低于1 mg/kg S.C.的剂量下，可显著降低MK-801(100微克/公斤S.C.)所致的空间工作记忆指标MK-801在8分钟的Y迷宫探索中的自发交替表现，但不影响伴随的超运动。DTG(100 mg/kg皮下注射)对小鼠的影响同时给予BMY 14802(10 mg/kg ip)可完全拮抗BMY 100的作用。和NE-100(1 mg/kg ip)，这两种可能的α拮抗剂单独作用不明显。在长时记忆测试(跳台型和穿透型被动回避、高架正迷宫)中，DTG在10和100微克/公斤体重的S.C.剂量下，对MK-801所致的记忆障碍有明显的抑制作用。在所有短期和长期记忆测试中，所测试的a配体的影响呈钟形曲线；1毫克/公斤没有影响。DTG不影响CPP(5 mg/kg，i.p)引起的交替损伤：这种调制可能选择性地以阻断NMDA受体相关离子通道为靶点。DTG(1-1000µg/kg)不影响东莨菪碱(1 mg/kg，i.p)所致的损伤。或地西潘(4 mg/kg ip)，但可明显阻止甲基苯丙胺(10 mg/kg ip)所致的损伤。这些结果表明，a配体对NMDA受体介导的谷氨酸能神经传递的增强作用，可能与海马区的学习和记忆过程有关。类似的调节也可能影响胆碱能尼古丁系统。
The potentiating effect of low doses of a ligands on the N-methyl-D-aspartate (NMDA)-induced excitation of pyramidal CA3 dorsal hippocampal neurons has recently been reported. In the present study, we investigated behavioral effects relevant to these findings in the experimental amnesia induced by the non-competitive NMDA antagonist, dizocilpine (MK-801), in mice. At doses below 1 mg/kg s.c., the sigma ligands, 1,3-di-(2-tolyl)guanidine (DTG), (+)-SKF 10,047, and (+)-pentazocine, but not their (-)-isomers, significantly decreased MK-801 (100 mu g/kg s.c.)-induced impairment of spontaneous alternation performances in 8-min sessions of a Y-maze exploration, an index of spatial working memory, without affecting the concomitant hyperlocomotion. The effect of DTG (100 mu g/kg s.c.) was completely antagonized by the simultaneous administration of BMY 14802 (10 mg/kg i.p.) and NE-100 (1 mg/kg i.p.), two putative a antagonists, which had no effect by themselves. In long-term memory tests (step-down and step-through types of passive avoidance, elevated plus-maze), DTG exhibited a significant attenuation of MK-801-induced amnesia, at doses of 10 and 100 mu g/kg s.c. In all tests of short- and long-term memory, the effects exhibited by the a ligands tested had a bell-shaped curve; no effect was seen at 1 mg/kg. DTG did not affect the impairment of alternation induced by CPP (5 mg/kg i.p.): the modulation may selectively target the blockade of NMDA receptor-associated ion channels. Moreover, DTG (1-1000 mu g/kg) did not affect the impairment induced by scopolamine (1 mg/kg i.p.) or diazepam (4 mg/kg i.p.), but significantly prevented the impairment induced by mecamylamine (10 mg/kg i.p.). These results suggest that the potentiating effect of a ligands on NMDA receptor-mediated glutamatergic neurotransmission, already demonstrated electrophysiologically, may have some relevance to learning and memory processes in the hippocampus. A similar modulation may also affect cholinergic nicotinic systems.