Ondansetron results in improved auditory gating in DBA/2 mice through a cholinergic mechanism.
Ondansetron results in improved auditory gating in DBA/2 mice through a cholinergic mechanism.
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DOI：
10.1016/j.brainres.2009.08.075
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发表时间：
2009-12-01
期刊：
影响因子：
2.9
通讯作者：
Stevens KE
中科院分区：
文献类型：
--
作者：
Wildeboer KM;Zheng L;Choo KS;Stevens KE
5-HT3受体拮抗剂恩丹西酮已被证明可以纠正药物治疗精神分裂症患者的听觉门控缺陷。抑制5-HT3受体释放乙酰胆碱，这是烟碱型乙酰胆碱受体的内源性配体。精神分裂症相关的听觉门控缺陷部分由烟碱型乙酰胆碱受体调节，小鼠(DBA/2)的缺陷模型也是如此。本研究评估了急性和长期给药恩丹西酮对DBA/2小鼠听觉门控的影响。听觉门控被定义为对初始听觉刺激后0.5秒出现的成对相同听觉刺激中的第二个刺激的反应幅度的降低。急性给予恩丹西酮最低剂量(0.1 mg/kg，ip)无作用，而其他剂量(0.33和1 mg/kg，ip)对听门有改善作用。这些改善是通过增加对第一个听觉刺激的反应和减少对第二个听觉刺激的反应来实现的。α-7烟碱型乙酰胆碱受体拮抗剂α-银环蛇毒素或α-4-β-2烟碱型乙酰胆碱受体拮抗剂二氢-β-红景天定与0.33 mg/kg剂量的恩丹西酮合用可阻断单用恩丹西酮对听性门控的改善。长期注射的小鼠和幼稚的小鼠之间的反应没有差异。两者都表现出改善的听觉门控，因此没有显示出每日注射的“遗留”效应。这些数据表明，恩丹西酮间接刺激烟碱型乙酰胆碱受体可以改善DBA/2小鼠的听觉门控参数。
The 5-HT3 receptor antagonist, ondansetron, has been shown to correct the auditory gating deficit in medicated schizophrenia patients. Inhibition of 5-HT3 receptors releases acetylcholine, the endogenous ligand for nicotinic acetylcholine receptors. The schizophrenia-related auditory gating deficit is modulated, in part, by nicotinic acetylcholine receptors, as is the mouse (DBA/2) model of the deficit. The present study assessed the effects of both acute and chronically administered ondansetron on auditory gating in DBA/2 mice. Auditory gating is defined as a decrease in amplitude of response to the second of a paired identical auditory stimulus presented 0.5 seconds following an initial auditory stimulus. Acute ondansetron administration at the lowest dose (0.1 mg/kg, IP) tested had no effect, while other doses (0.33 and 1 mg/kg, IP) produced improvements in auditory gating. The improvements were produced through both an increase in response to the first auditory stimulus and a decrease in the response to the second auditory stimulus. Co-administration of an α7 nicotinic acetylcholine receptor antagonist, α-bungarotoxin, or the α4β2 nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, with the 0.33 mg/kg dose of ondansetron blocked the improvement in auditory gating produced by ondansetron alone. There was no difference in response between the chronically injected mice and naïve mice. Both showed improved auditory gating, thus, demonstrating no “carry over” effect of daily injections. These data demonstrate that indirect stimulation of nicotinic acetylcholine receptors by ondansetron can improve auditory gating parameters in DBA/2 mice.
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