Department of Pharmacology, The Medical School, University Walk, Bristol.
J Psychopharmacol. 1987 Jan;1(1):35-46. doi: 10.1177/026988118700100108.
Drugs acting at benzodiazepine receptors can have two types of pharmacological profile: benzodiazepine agonists are anxiolytic, anticonvulsant and sedative, whilst benzo diazepine inverse agonists cause anxiety and convulsions. In 1982 we showed that a benzo diazepine antagonist, Ro 15-1788, prevented the effects of both types of compound at doses without intrinsic activity in the tests used. We put forward the hypothesis that the benzo diazepine receptor complex could undergo two possible conformational changes, resulting in increases (benzodiazepine agonists) or decreases (benzodiazepine inverse agonists) in the effects of the inhibitory transmitter γ-aminobutyric acid (GABA). This concept has been widely accepted. We have now studied the effects of inverse agonists after chronic treatment with inverse agonists themselves and with benzodiazepine agonists, in order to see if tolerance develops (as seen with the agonists) or whether an opposite change occurs.
作用于苯二氮䓬受体的药物具有两种类型的药理学特征：苯二氮䓬激动剂具有抗焦虑、抗惊厥和镇静作用，而苯二氮䓬反向激动剂则引起焦虑和惊厥。1982 年，我们表明，苯二氮䓬拮抗剂 Ro 15-1788 在没有内在活性的剂量下，可以预防这两种化合物在所用测试中的作用。我们提出假设，苯二氮䓬受体复合物可能发生两种可能的构象变化，导致抑制性递质γ-氨基丁酸（GABA）的作用增加（苯二氮䓬激动剂）或减少（苯二氮䓬反向激动剂）。这个概念已经被广泛接受。我们现在已经研究了在慢性使用反向激动剂本身和苯二氮䓬激动剂后，反向激动剂的作用，以观察是否会产生耐受性（如激动剂所见），或者是否会发生相反的变化。
