Georgopoulos Panagiotis, Petrides Theodoros, Kostopoulos George, Papatheodoropoulos Costas
Department of Physiology, Medical School, University of Patras, 26 504 Patras, Greece.
Brain Res. 2008 May 1;1207:43-59. doi: 10.1016/j.brainres.2008.02.017.
The positive modulation of the GABA(A) receptor (GABA(A)R) is presumably one of the main mechanisms by which several sedatives mediate their actions in the central nervous system. This modulation appears to depend on the presence of alpha and beta GABA(A)R subunits, whose distinct expression in dorsal and ventral hippocampus has been recently shown. Using population spike recordings from the CA1 area of dorsal (DHS) and ventral (VHS) hippocampal slices we compared the effects of seven sedative/anesthetic drugs (diazepam, midazolam, phenobarbital, propofol, pentobarbital, thiopental and alfaxalone) on the GABAergic recurrent inhibition (RI) between the two hippocampal poles. The strength and duration of RI was quantified by measuring an antidromic stimulation-induced suppression of the orthodromic population spike at varying inter-pulse intervals. All drugs enhanced RI in both DHS and VHS but high concentrations of barbiturates and alfaxalone prolonged RI considerably more compared to benzodiazepines or low doses of barbiturates and propofol. Furthermore, the drug-induced prolongation of RI was significantly greater in DHS than in VHS. Thus, RI was enhanced by thiopental (50 microM), alfaxalone (2.5 microM) and pentobarbital (50 microM) up to 150 ms, 150 ms and 270 ms respectively in DHS, and up to 70 ms, 100 ms and 150 ms respectively in VHS. In addition, under GABA(B) receptor blockade, thiopental (100 microM) and alfaxalone (10 microM) prolonged GABA(A)R-mediated RI significantly more in DH (up to 900 ms) than in VH (up to 430 ms and 600 ms respectively). This finding provides support to the notion of diversification of intrinsic organization along the septotemporal axis of the hippocampus. Finally, an interesting link was revealed between the magnitude of drug-induced enhancement of RI and the reported sedative potency of the drugs used, suggesting that deep sedation and anesthesia may involve prolongation of GABAergic inhibition.
γ-氨基丁酸A受体（GABA(A)R）的正向调节可能是几种镇静剂在中枢神经系统中介导其作用的主要机制之一。这种调节似乎取决于α和β GABA(A)R亚基的存在，最近已表明它们在背侧和腹侧海马体中有不同的表达。我们使用来自背侧（DHS）和腹侧（VHS）海马体切片CA1区域的群体峰电位记录，比较了七种镇静/麻醉药物（地西泮、咪达唑仑、苯巴比妥、丙泊酚、戊巴比妥、硫喷妥钠和阿法沙龙）对两个海马极之间GABA能反馈抑制（RI）的影响。通过测量在不同脉冲间隔下逆向刺激诱导的顺向群体峰电位的抑制来量化RI的强度和持续时间。所有药物均增强了DHS和VHS中的RI，但与苯二氮䓬类药物或低剂量巴比妥类药物和丙泊酚相比，高浓度的巴比妥类药物和阿法沙龙使RI延长得更多。此外，药物诱导的RI延长在DHS中比在VHS中显著更大。因此，硫喷妥钠（50μM）、阿法沙龙（2.5μM）和戊巴比妥（50μM）分别使DHS中的RI增强至150ms、150ms和270ms，使VHS中的RI分别增强至70ms、100ms和150ms。此外，在GABA(B)受体阻断下，硫喷妥钠（100μM）和阿法沙龙（10μM）使DH中GABA(A)R介导的RI延长（长达900ms）比VH中（分别长达430ms和600ms）显著更多。这一发现为海马体沿颞叶轴内在组织多样化的观点提供了支持。最后，揭示了药物诱导的RI增强幅度与所用药物报告的镇静效力之间的有趣联系，表明深度镇静和麻醉可能涉及GABA能抑制的延长。
