Gellman R L, Aghajanian G K
Department of Psychiatry, Yale University School of Medicine, New Haven, CT.
Neuroscience. 1994 Feb;58(3):515-25. doi: 10.1016/0306-4522(94)90077-9.
Rat piriform cortex contains a subpopulation of presumed GABAergic interneurons located near the border of layers 2 and 3 that express excitatory serotonin2 receptors. These serotonin2-responsive interneurons send axons to layer 2 pyramidal cells. Using an in vitro brain slice preparation, serotonin2 receptor-mediated excitation can be assessed either by directly recording from the interneurons or by recording the increase in inhibitory postsynaptic potentials in the pyramidal cells. Intracellular recordings from the interneurons demonstrated that compared to pyramidal cells they had a more depolarized resting membrane potential, a higher input resistance and shorter action potential duration. The serotonin2 receptor-mediated excitation was associated with a strong depolarization (range 3-22 mV). We found that the atypical antipsychotic drugs, risperidone and clozapine, which have relatively high affinity for serotonin2 receptors, each dose-dependently inhibited the serotonin2-mediated excitation of the interneurons with IC50 values of 7 nM and 1.4 microM, respectively. This antagonism was specific to the extent that excitation mediated by agonists at excitatory amino acid receptors were not blocked at concentrations of risperidone and clozapine that completely antagonized the serotonin2 receptor-mediated excitation. The typical antipsychotic drug, chlorpromazine, inhibited the serotonin2-mediated excitation of the interneurons with an IC50 of 14 microM. Haloperidol, another typical antipsychotic drug, decreased the serotonin2 response to about half of baseline at a concentration of 10 microM (the exact IC50 could not be calculated because higher concentrations produced non-specific effects on cells). Both risperidone and clozapine blocked the serotonin-elicited inhibitory postsynaptic potentials in layer 2 pyramidal cells at concentrations that approximated the IC50 for antagonizing the serotonin2-mediated excitation of the interneurons. Chlorpromazine and haloperidol, in the concentration range that blocked serotonin2 receptor-mediated excitation of interneurons, also blocked the serotonin-elicited inhibitory postsynaptic potentials in the pyramidal cells. The IC50 values for risperidone and clozapine, but not for chlorpromazine or haloperidol, for blocking serotonin2 receptor-mediated actions in rodent piriform cortical slice are in the range of the plasma concentrations of the drug that are clinically efficacious. Our data suggest that a potential site of action of the atypical antipsychotic drugs risperidone and clozapine could be antagonism of serotonin acting through serotonin2 receptors on GABAergic interneurons in cerebral cortex.
大鼠梨状皮质包含一群假定的γ-氨基丁酸能中间神经元，它们位于第2层和第3层边界附近，表达兴奋性5-羟色胺2受体。这些对5-羟色胺2有反应的中间神经元将轴突发送至第2层锥体细胞。使用体外脑片制备技术，5-羟色胺2受体介导的兴奋作用可以通过直接记录中间神经元的活动或记录锥体细胞中抑制性突触后电位的增加来评估。对中间神经元进行细胞内记录表明，与锥体细胞相比，它们具有更去极化的静息膜电位、更高的输入电阻和更短的动作电位持续时间。5-羟色胺2受体介导的兴奋作用与强烈的去极化（范围为3 - 22毫伏）相关。我们发现，对5-羟色胺2受体具有相对较高亲和力的非典型抗精神病药物利培酮和氯氮平，各自均呈剂量依赖性地抑制中间神经元的5-羟色胺2介导的兴奋作用，IC50值分别为7纳摩尔和1.4微摩尔。这种拮抗作用具有特异性，即在利培酮和氯氮平完全拮抗5-羟色胺2受体介导的兴奋作用的浓度下，兴奋性氨基酸受体激动剂介导的兴奋作用并未被阻断。典型抗精神病药物氯丙嗪抑制中间神经元的5-羟色胺2介导的兴奋作用，IC50为14微摩尔。另一种典型抗精神病药物氟哌啶醇在浓度为10微摩尔时，将5-羟色胺2反应降低至基线的约一半（由于更高浓度对细胞产生非特异性作用，无法计算确切的IC50）。利培酮和氯氮平在接近拮抗中间神经元的5-羟色胺2介导的兴奋作用的IC50的浓度下，均阻断了第2层锥体细胞中5-羟色胺引发的抑制性突触后电位。氯丙嗪和氟哌啶醇在阻断中间神经元的5-羟色胺2受体介导的兴奋作用的浓度范围内，也阻断了锥体细胞中5-羟色胺引发的抑制性突触后电位。利培酮和氯氮平在啮齿动物梨状皮质切片中阻断5-羟色胺2受体介导的作用的IC50值，处于临床上有效的药物血浆浓度范围内。我们的数据表明，非典型抗精神病药物利培酮和氯氮平的一个潜在作用位点可能是拮抗5-羟色胺通过大脑皮质中γ-氨基丁酸能中间神经元上的5-羟色胺2受体所发挥的作用。
