Chronic inhibition of α4β2 nicotinic receptors in the ventral hippocampus of rats:: impacts on memory and nicotine response
Chronic inhibition of α4β2 nicotinic receptors in the ventral hippocampus of rats:: impacts on memory and nicotine response
复制标题
DOI：
10.1007/s00213-001-0961-6
复制
发表时间：
2002-03-01
影响因子：
3.4
通讯作者：
Levin, ED
中科院分区：
文献类型：
--
作者：
Arthur, D;Levin, ED
理论基础：急性和慢性全身应用尼古丁已被证明能显著改善空间记忆。这种作用的关键尼古丁受体亚型及其位置仍在确定中。腹侧海马区的尼古丁受体被发现与记忆密切相关。在辐射警报迷宫中，向大鼠海马区急性腹侧注入二氢-β-红景天定(DHBetaE)--一种α-β-2烟碱受体拮抗剂--可损害大鼠的空间记忆。目的：本研究使用慢性腹侧海马区注射DHBetaE作为烟碱受体丢失的模型，如阿尔茨海默病。测定全身尼古丁治疗对DHBetaE所致记忆障碍的逆转作用。方法：对大鼠进行八臂径向迷宫训练，使其在八臂径向迷宫中表现出渐近水平。然后，在腹侧海马区植入双侧输液管，连续输注DHBetaE 0、33.3或100µg/侧/天，持续4周。在灌注期和停药后，在八臂迷宫上对大鼠进行复测，并检测急性全身注射尼古丁对记忆的影响。结果：DHBetaE剂量越大(100杯/边/天)，DHBetaE剂量越低(33.3杯/边/天)，空间记忆障碍越明显。急性全身注射尼古丁(0，0.1，0.2和0.4 mg/kg，皮下)可减弱100杯/侧/天的DHBetaE的记忆损害效应。慢性注射DHbetaE对反应潜伏期无明显影响。急性全身性尼古丁注射显著加快了反应速度，这一效应被慢性注射DHBetaE的海马区逆转。戒断后，对选择的准确性或反应潜伏期没有显著的持久影响。在慢性给予海马区DHBetaE期间，湿狗抖动显著增加，但在戒断期间没有影响。结论：这些结果表明，海马区烟碱受体亚群的慢性抑制导致空间记忆选择准确性的显著损害。尼古丁减轻损伤的能力支持尼古丁激动剂治疗阿尔茨海默病等综合症的发展，这些综合症涉及α4β2尼古丁受体活性的慢性降低和记忆障碍。
Rationale: Acute and chronic systemic nicotine administration has been shown to cause significant spatial memory improvement. The critical nicotinic receptor subtypes for this effect and their location are still being determined. Nicotinic receptors in the ventral hippocampus have been found to be critically involved in memory. Acute ventral hippocampal infusions of dihydro-beta-erythroidine (DHBetaE), an alpha4beta2 nicotinic receptor antagonist, impaired spatial memory of rats in the radialarm maze. Objectives: The current study used chronic ventral hippocampal infusion of DHBetaE as a model of nicotinic receptor loss such as that which occurs in Alzheimer's disease. The therapeutic effect of systemic nicotine treatment in reversing the DHBetaE-induced memory impairment was determined. Methods: Rats were pretrained to asymptotic levels of performance on the eight-arm radial maze. Then, they were implanted with bilateral infusion cannulae in the ventral hippocampus, through which 0, 33.3, or 100 mug/side/day of DHBetaE was continuously infused for 4 weeks. The rats were retested on the eight-arm maze throughout infusion period and after C withdrawal, and the interaction of acute systemic nicotine injections on memory was tested. Results: The higher (100 mug/side/day) but not the lower (33.3 mug/side/day) DHBetaE dose caused a significant spatial memory impairment. Acute systemic nicotine injections (0, 0.1, 0.2, and 0.4 mg/kg, subcutaneous) attenuated the memory impairing effects of 100 mug/side/day of DHBetaE. There was no significant effect on response latency with the chronic DHbetaE infusion. Acute systemic nicotine infusions did significantly speed responding, an effect which was reversed by chronic hippocampal infusions of DHBetaE. After withdrawal there were no significant lasting effects on choice accuracy or response latency. Wet-dog shakes were significantly elevated during chronic hippocampal DHBetaE administration with no effect during the withdrawal period. Conclusions: These results indicate that chronic inhibition of a subset of nicotinic receptors in the hippocampus results in a significant impairment in the spatial memory choice accuracy. The ability of nicotine to attenuate the impairment supports the development of nicotinic agonist therapy of syndromes, such as Alzheimer's disease, that involve a chronic decrease in the activity of the alpha4beta2 nicotinic receptors and memory impairment.