title: Mechanism of bis(7)-tacrine inhibition of GABA-activated current in cultured rat hippocampal neurons.
abstract: Bis(7)-tacrine is a novel dimeric acetylcholinesterase inhibitor derived from tacrine that shows promise for the treatment of Alzheimer's disease. We have previously reported that bis(7)-tacrine inhibits GABA(A) receptors. In the present study we investigated the mechanism of bis(7)-tacrine inhibition of GABA(A) receptor function using whole-cell patch-clamp recording in cultured rat hippocampal neurons. Bis(7)-tacrine produced a gradual decline of GABA-activated current to a steady-state, but this was not an indication of use-dependence, as the gradually declining component could be eliminated by exposure to bis(7)-tacrine prior to GABA application. In addition, bis(7)-tacrine inhibition did not require the presence of agonist, and GABA-activated current recovered completely from inhibition by bis(7)-tacrine in the absence of agonist. The slow onset of inhibition by bis(7)-tacrine was not apparently due to an action at an intracellular site, as inclusion of 25 microM bis(7)-tacrine in the recording pipette did not alter inhibition by bis(7)-tacrine applied externally. Bis(7)-tacrine shifted the GABA concentration-response curve to the right in a parallel manner and the pA(2) value estimated from a Schild plot was 5.7. Bis(7)-tacrine increased the time constant of activation of GABA-gated ion channels without affecting the time constants of deactivation or desensitization. These results suggest that bis(7)-tacrine is a competitive GABA(A) receptor antagonist with slow onset and offset kinetics. The competitive inhibition of GABA receptors by bis(7)-tacrine could contribute to its ability to enhance memory.
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Liu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Peoples
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Xiang
authors.initials: X
authors.lastname: Tian
authors.forename: Yong-Xun
authors.initials: YX
authors.lastname: Ai
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
authors.forename: Zhi-Wang
authors.initials: ZW
authors.lastname: Li
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Han
authors.forename: Chao-Ying
authors.initials: CY
authors.lastname: Li
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D004791:Enzyme Inhibitors; D013619:Tacrine; D005680:gamma-Aminobutyric Acid