Effects of lorazepam tolerance and withdrawal on GABAA receptor operated chloride channels in mice selected for differences in ethanol withdrawal severity.
Effects of lorazepam tolerance and withdrawal on GABAA receptor operated chloride channels in mice selected for differences in ethanol withdrawal severity.
复制标题
劳拉西泮耐受性和戒断对因乙醇戒断严重程度不同而选择的小鼠中 GABAA 受体操作的氯离子通道的影响。
DOI：
10.1016/0024-3205(92)90401-a
复制
发表时间：
1992
期刊：
影响因子：
6.1
通讯作者：
Zhang,X
中科院分区：
文献类型：
--
作者：
Allan,AM;Baier,LD;Zhang,X
通过植入的渗透微型泵，用5 mg/kg劳拉西泮治疗易戒断性癫痫发作（WSP）和戒断性癫痫发作抵抗（WSR）小鼠7天。在长期药物治疗后，分析大脑的GABA介导的氯离子通量（GABA-Cl−）。在对照（未用药）条件下，从WSP和WSR细胞系制备的脑细胞膜在氟硝西泮或乙醇刺激GABA介导的36 Cl −摄取方面没有差异，但WSP细胞系对反向激动剂FG-7142抑制36 Cl −通量更敏感。劳拉西泮耐受WSP和WSR小鼠的膜对氟硝西泮和乙醇刺激的GABA-Cl−具有抗性。通过急性注射苯二氮卓类拮抗剂RO 15 -1788从慢性治疗中退出，使WSR膜中GABA-Cl−的氟硝西泮刺激恢复至接近对照水平，但WSP膜中未恢复，并使两条线路中通道的乙醇调节恢复至对照水平。与WSR小鼠相比，苯二氮卓类部分反向激动剂FG-7142对WSP小鼠膜中氯离子通量的抑制作用更大。对劳拉西泮的耐受性增加了WSR膜对FG-7142的敏感性，而不改变WSP系的反应。同样，停药使FG-7142的Cl−通量响应恢复到接近对照水平。劳拉西泮耐受性仅在WSR菌株中略微降低[3 H]-氟硝西泮结合亲和力，结合数无变化。退出慢性劳拉西泮治疗产生的结合亲和力或数量没有显着变化。苯二氮卓类反向激动剂敏感性的初始基因型差异可能与戒断发作严重程度的选择有关。劳拉西泮的长期给药降低了苯二氮卓类激动剂位点和氯离子通道之间的偶联，同时增加了通道和反向激动剂位点之间的偶联，而戒断则将受体偶联重置回对照反应水平。然而，对于WSP线，与WSR线相比，通道耦合偏置中的这种药物环境依赖性转变似乎是不足的。
Withdrawal seizure prone (WSP) and withdrawal seizure resistant (WSR) mice were treated with 5 mg/kg lorazepam for 7 days via implanted osmotic mini pumps. Following chronic drug treatment, brains were assayed for GABA-mediated chloride flux (GABA-Cl−). Under control (drug naive) conditions, brain membranes prepared from WSP and WSR lines did not differ in flunitrazepam or ethanol stimulation of GABA-mediated36Cl−uptake, but the WSP lines were more sensitive to inhibition of36Cl−flux by the inverse agonist, FG-7142. Membranes from lorazepam tolerant WSP and WSR mice were resistant to flunitrazepam- and ethanol-stimulation of GABA-Cl−. Withdrawal from chronic treatment, by an acute injection with the benzodiazepine antagonist RO15-1788, returned flunitrazepam stimulation of GABA-Cl−to near control levels in WSR membranes but not in WSP membranes and restored ethanol modulation of the channel to control levels in both lines. Inhibition of chloride flux by the benzodiazepine partial inverse agonist, FG-7142 was greater in membranes from WSP mice compared with WSR mice. Tolerance to lorazepam increased sensitivity of the WSR membranes to FG-7142 without altering the response in the WSP line. Again, withdrawal restored the Cl−flux response to FG-7142 back to near control levels. Lorazepam tolerance lowered [3H]-flunitrazepam binding affinity slightly only in the WSR strain with no change in binding number. Withdrawal from chronic lorazepam treatment produced no significant change in binding affinity or number. The initial genotypic differences in benzodiazepine inverse agonist sensitivity, may be related to the selection for withdrawal seizure severity. Chronic administration of lorazepam reduces the coupling between the benzodiazepine agonist site and the chloride channel and concomitantly increases coupling between the channel and the inverse agonist site, while withdrawal resets the receptor coupling back to control response levels. However, for the WSP line, this drug environment dependent shift in channel coupling bias appears to be deficient compared with the WSR line.