Koe B K, Kondratas E, Russo L L
Department of Pharmacology, Pfizer Inc., Groton, CT 06340.
Eur J Pharmacol. 1987 Oct 27;142(3):373-84. doi: 10.1016/0014-2999(87)90076-8.
Administration of the benzodiazepine receptor antagonist, [3H]Ro 15-1788, to mice intravenously was found to label these receptors in brain. Binding of [3H]Ro 15-1788 in vivo was strongly blocked by pretreating mice with clonazepam or diazepam. Marked enhancement of [3H]Ro 15-1788 binding in vivo was induced by progabide or sodium valproate. This effect was greater than a similar enhancement of [3H]flunitrazepam binding. The increased membrane-bound [3H]Ro 15-1788 elicited by progabide was completely dissociated on subsequent incubation with Ro 15-1788, diazepam or clobazam, indicating that the enhanced binding occurred at benzodiazepine receptors. Compounds that exert diazepam-like actions and/or indirect GABAergic activity (cartazolate, pentobarbital, methaqualone, levonantradol, phenytoin) elicited enhancement of [3H]Ro 15-1788 in vivo. Other CNS agents (atypical neuroleptics, GABA antagonists, baclofen, some 5-HT1 agonists) also induced elevation of [3H]Ro 15-1788 binding in vivo, as did drugs exerting vasodilatatory effects (papaverine, nimodipine, verapamil, prazosin, N6-cyclohexyladenosine). Possible explanations for enhancement of [3H]Ro 15-1788 binding in vivo include increase in the number of benzodiazepine receptors induced by GABA or GABAergic drugs or effects of binding enhancers that elevate brain levels of [3H]Ro 15-1788, such as accelerating cerebral blood flow, competing for radioligand binding sites in plasma or increasing metabolic stability of the radioligand.
静脉注射苯二氮䓬受体拮抗剂[3H]Ro 15 - 1788后，发现其可标记小鼠脑中的这些受体。用氯硝西泮或地西泮预处理小鼠可强烈阻断[3H]Ro 15 - 1788在体内的结合。丙戊酸或普加巴林可诱导[3H]Ro 15 - 1788在体内的结合显著增强。这种作用比[3H]氟硝西泮结合的类似增强作用更强。普加巴林引起的膜结合[3H]Ro 15 - 1788增加在随后与Ro 15 - 1788、地西泮或氯巴占孵育时完全解离，表明增强的结合发生在苯二氮䓬受体处。具有地西泮样作用和/或间接GABA能活性的化合物（卡他唑酯、戊巴比妥、甲喹酮、左南曲朵、苯妥英）在体内可引起[3H]Ro 15 - 1788结合增强。其他中枢神经系统药物（非典型抗精神病药、GABA拮抗剂、巴氯芬、一些5 - HT1激动剂）以及具有血管舒张作用的药物（罂粟碱、尼莫地平、维拉帕米、哌唑嗪、N6 - 环己基腺苷）在体内也可诱导[3H]Ro 15 - 1788结合升高。[3H]Ro 15 - 1788在体内结合增强的可能解释包括GABA或GABA能药物诱导的苯二氮䓬受体数量增加，或结合增强剂的作用，这些增强剂可提高脑中[3H]Ro 15 - 1788的水平，如加速脑血流、竞争血浆中的放射性配体结合位点或增加放射性配体的代谢稳定性。
