Neurotoxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, The Netherlands.
Neurotoxicology. 2011 Dec;32(6):823-7. doi: 10.1016/j.neuro.2011.05.016. Epub 2011 Jun 25.
Drugs of abuse are known to mainly affect the dopaminergic and serotonergic system, although behavioral studies indicated that the GABA-ergic system also plays a role. We therefore investigated the acute effects of several commonly used drugs of abuse (methamphetamine, amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and meta-chlorophenylpiperazine (mCPP)) on the function of the human α(1)β(2)γ(2) GABA(A) receptor (hGABA(A)-R), expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. Although none of the tested drugs acted as full agonist on the hGABA(A)-R, some drugs induced differential modulation of hGABA(A)-R function, depending on the degree of receptor occupancy. Methamphetamine did not affect the GABA-evoked current at high receptor occupancy, but induced a minor inhibition at low receptor occupancy. Its metabolite amphetamine slightly potentiated the GABA-evoked current. MDMA and its metabolite MDA both inhibited the current at low receptor occupancy. However, MDMA did not affect the current at high occupancy, whereas MDA induced a potentiation. mCPP induced a strong inhibition (max. ∼ 80%) at low receptor occupancy, but ∼ 25% potentiation at high receptor occupancy. Competitive binding to one of the GABA-binding sites could explain the drug-induced inhibitions observed at low receptor occupancy, whereas an additional interaction with a positive allosteric binding site may play a role in the observed potentiations at high receptor occupancy. This is the first study to identify direct modulation of hGABA(A)-Rs as a novel mode of action for several drugs of abuse. Consequently, hGABA(A)-Rs should be considered as target for psychiatric pharmaceuticals and in developing treatment for drug intoxications.
滥用药物主要影响多巴胺能和血清素能系统，尽管行为研究表明 GABA 能系统也发挥作用。因此，我们使用双电极电压钳技术，研究了几种常用的滥用药物（甲基苯丙胺、苯丙胺、3,4-亚甲基二氧基甲基苯丙胺（MDMA）、3,4-亚甲基二氧基苯丙胺（MDA）和间氯苯哌嗪（mCPP））对表达在非洲爪蟾卵母细胞中的人 α(1)β(2)γ(2)GABA(A)受体 (hGABA(A)-R) 功能的急性影响。虽然测试的药物没有一种对 hGABA(A)-R 表现出完全激动剂的作用，但有些药物根据受体占有率的不同，对 hGABA(A)-R 功能产生不同的调节作用。甲基苯丙胺在高受体占有率时不会影响 GABA 诱发的电流，但在低受体占有率时会引起轻微抑制。其代谢物苯丙胺轻微增强 GABA 诱发的电流。MDMA 和其代谢物 MDA 都在低受体占有率时抑制电流。然而，MDMA 对高占有率的电流没有影响，而 MDA 则引起增强。mCPP 在低受体占有率时引起强烈抑制（最大约 80%），但在高受体占有率时约有 25%的增强。对一个 GABA 结合位点的竞争性结合可以解释在低受体占有率时观察到的药物诱导抑制，而在高受体占有率时观察到的增强可能与另外的正变构结合位点相互作用有关。这是首次报道几种滥用药物作为新型作用模式直接调节 hGABA(A)-Rs。因此，hGABA(A)-Rs 应该被视为精神药物的靶点，并用于开发治疗药物中毒的方法。
