New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (ω) receptor subtypes
New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (ω) receptor subtypes
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DOI：
10.1007/s002130051108
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发表时间：
1999-09-01
影响因子：
3.4
通讯作者：
Sanger, DJ
中科院分区：
文献类型：
--
作者：
Griebel, G;Perrault, G;Sanger, DJ
理论基础：已有研究表明，不同的BZ(Omega)受体亚型可能介导不同的BZ受体配体的行为效应。目的：本研究进一步验证了这一假设。方法：在行为学、生物化学和电生理实验中，观察选择性BZ(1)(omega(1))受体拮抗剂β-CCT对选择性BZ(1)(omega(1))受体激动剂唑吡坦和非选择性BZ(omega(1))受体激动剂安定的药理作用。结果：本身无活性的β-CCT可拮抗非选择性BZ(Omega)受体全激动剂地西潘和选择性BZ(1)(omega(1))受体全激动剂唑吡坦对异烟肼所致惊厥的作用，但不影响其对戊四氮(PTZ)所致惊厥的作用，提示BZ(2)(omega(2))受体可能主要参与PTZ的惊厥作用。在明/暗试验中，β-CCT取消了地西潘的抗焦虑作用。在研究药物中枢抑制活性的实验中，β-CCT拮抗地西潘和唑吡坦的镇静作用，但不能明显改变地西潘的肌松作用。这些差异可能与β-CCT对BZ(1)(omega(1))位点的选择性有关，与小鼠体内Bz(2)(omega(2))富集型结构相比，[H-3]flumazenil在BZ(1)(omega(1))富集型结构中优先置换。在体外实验中，β-CCT在表达α(1)β(2)γ(2)受体的HEK细胞或小脑浦肯野神经元中拮抗由唑吡坦产生的氯离子电流的增强，但不能改变α(3)β(2)伽马(2)或α(5)β(3)伽马(2)受体亚型对地西潘的增强作用。结论：BZ(1)(Omega)受体在BZ(Omega)受体配体的抗焦虑和镇静/催眠作用中起重要作用，而Bz(2)(omega(2))部位的活性可能主要与肌肉松弛有关。
Rationale: It has been suggested that different BZ (omega) receptor subtypes may mediate distinct behavioural effects of BZ receptor ligands. Objective: The present study examined this hypothesis further. Methods: The antagonism exerted by the selective BZ(1) (omega(1)) receptor antagonist beta-CCT on the pharmacological effects of the selective BZ(1) (omega(1)) receptor agonist zolpidem and the non-selective BZ (omega) receptor agonist diazepam in behavioural, biochemical and electrophysiological experiments was assessed. Results: beta-CCT which was devoid of activity per se, antagonized the effects of the non-selective BZ (omega) receptor full agonist diazepam and the selective BZ(1) (omega(1)) receptor full agonist zolpidem against seizures produced by isoniazid, but beta-CCT failed to affect their action on seizures produced by pentylenetetrazole (PTZ), suggesting that BZ(2) (omega(2)) receptors may be primarily involved in the convulsant action of PTZ. In the light/dark test, beta-CCT abolished the anxiolytic-like action of diazepam. In tests designed to investigate the central depressant activity of drugs, beta-CCT antagonized the sedative effects of diazepam and zolpidem, but failed to modify clearly the myorelaxant effects of diazepam. These differences may be related to the selectivity of beta-CCT for BZ(1) (omega(1)) sites as indicated by the preferential displacement of [H-3]flumazenil in BZ(1) (omega(1))-enriched structures as compared to BZ(2) (omega(2))-enriched structures in the mouse. In in vitro experiments, beta-CCT antagonized the potentiation of the GABA-induced Cl- current produced by zolpidem in HEK cells expressing the alpha(1)beta(2)gamma(2) receptor or in cerebellar Purkinje neurones, while it failed to modify the diazepam potentiation at either alpha(3)beta(2)gamma(2) or alpha(5)beta(3)gamma(2) receptor subtypes. Conclusion: These results are consistent with the hypothesis that BZ(1) (omega) receptors play an important role in the anxiolytic and sedative/hypnotic effects of BZ (omega) receptor ligands, whereas activity at BZ(2) (omega(2)) sites might be associated primarily with muscle relaxation.