Reduction of GABA-mediated inhibitory postsynaptic potentials in hippocampal CA1 pyramidal neurons following oral flurazepam administration.
Reduction of GABA-mediated inhibitory postsynaptic potentials in hippocampal CA1 pyramidal neurons following oral flurazepam administration.
复制标题
口服氟西泮后海马 CA1 锥体神经元 GABA 介导的抑制性突触后电位减少。
DOI：
10.1016/0306-4522(94)00558-m
复制
发表时间：
1995
期刊：
影响因子：
3.3
通讯作者：
Tietz,EI
中科院分区：
文献类型：
--
作者：
Zeng,X;Xie,XH;Tietz,EI
口服苯二氮卓类、泮一周导致体内和体外耐受性，并导致海马CA 1锥体细胞区体外复发和前馈抑制减少。在本研究中，在停止口服泮治疗后2天或7天处死的大鼠海马切片（500 μm）中，在体外细胞内检查了CA 1锥体细胞。药物处理后，CA 1锥体细胞的膜特性与对照神经元无显著差异。GABAA介导的，早期抑制性突触后电位的幅度显着降低（60%），在锥体神经元的大鼠杀死两天，但不是在那些杀死7天后，结束给药。在早期抑制性突触后电位振幅的减少，观察到使用刚刚亚阈值，阈值和超大顺向刺激，以及以下逆向激活。早期抑制性突触后电位振幅的降低幅度在GABA A拮抗剂CGP 35348的存在下是相似的，并且不能归因于氟拉西泮治疗组和对照组之间传入刺激强度的差异。与对照细胞相比，GABAB介导的晚期抑制性突触后电位的大小也显著降低（45%）。两组之间早期（−72 mV）和晚期（−92 mV）超极化的恢复电位无显著差异。高强度顺向刺激后，在细胞内钠通道阻滞剂（QX-314）的存在下，也阻断GABAB介导的晚期超极化，荷包牡丹碱敏感的晚期去极化电位在FZP处理的大鼠神经元中被揭露，但从未从对照细胞。兴奋性突触后电位振幅显着增加，在氟拉西泮治疗的神经元和突触诱发的动作电位的阈值显着增加。去极化电流注入后，锥体细胞放电的持续时间和频率以及动作电位阈值没有改变口服泮治疗。快后超极化的幅度也没有改变。总体而言，研究结果表明，慢性苯二氮卓类药物治疗后，大鼠在体内耐受苯二氮卓类药物的抗惊厥作用时，GABA能突触向海马CA 1锥体细胞神经元的传递受损。
Oral administration of the benzodiazepine, flurazepam, for one week results in tolerance in vivo and in vitro and in a reduction in recurrent and feedforward inhibition in vitro in the CA1 pyramidal cell region of hippocampus. In the present study CA1 pyramidal cells were examined intracellularly in vitro in rat hippocampal slices (500 μm) from rats sacrificed two or seven days after cessation of oral flurazepam treatment. Following drug treatment, the membrane characteristics of CA1 pyramidal cells were not significantly different from control neurons. GABAA-mediated, early inhibitory postsynaptic potentials were significantly reduced in amplitude (60%) in pyramidal neurons from rats killed two days, but not in those killed seven days, after the end of drug administration. The decrease in early inhibitory postsynaptic potential amplitude was observed using just-subthreshold, threshold and supramaximal orthodromic stimulation as well as following antidromic activation. The magnitude of the decrease in the early inhibitory postsynaptic potential amplitude was similar in the presence of the GABABantagonist, CGP 35348, and could not be attributed to differences in the strength of afferent stimulation between flurazepam-treated and control groups. The size of the GABAB-mediated, late inhibitory postsynaptic potentials was also significantly decreased (45%) in comparison to control cells. Reversal potentials for both the early (−72 mV) and late (−92 mV) hyperpolarizations were not significantly different between groups. Following high intensity orthodromic stimulation, in the presence of an intracellular sodium channel blocker (QX-314) which also blocks the GABAB-mediated late hyperpolarization, a bicuculline-sensitive late depolarizing potential was unmasked in neurons from FZP-treated rats, but never from control cells. Excitatory postsynaptic potential amplitude was significantly increased in flurazepam-treated neurons and the threshold for the synaptically-evoked action potential was significantly increased. Following depolarizing current injection, the duration and frequency of pyramidal cell discharges and the action potential threshold were not altered by oral flurazepam treatment. The amplitude of the fast afterhyperpolarization was also not changed. Overall, the findings indicate an impairment of transmission at GABAergic synapses onto hippocampal CA1 pyramidal cell neurons after chronic benzodiazepine treatment at a time when rats are tolerant to the anticonvulsant effects of benzodiazepines in vivo.