Depoortere R, Perrault G, Sanger D J
Synthelabo Recherche, Bagneux, France.
Behav Pharmacol. 1997 Aug;8(4):364-72. doi: 10.1097/00008877-199708000-00009.
In a previous study using Sprague-Dawley rats, we showed that in a prepulse inhibition (PPI) procedure with levels of PPI ranging from approximately 10 to 40% (for prepulse intensities 2, 9 and 15 dB above background noise), the antipsychotics clozapine and haloperidol, but also the alpha 1 adrenoceptor antagonist prazosin, robustly and dose-dependently potentiated PPI. In contrast, the antipsychotics risperidone, amisulpride, raclopride and remoxipride did not potentiate PPI. The false positive (prazosin) and the four false negatives led us to conclude that this PPI-enhancing procedure had poor predictive validity as a screening tool for potential antipsychotics. In the present study, we used Wistar rats, which under the same protocol as that used for Sprague-Dawley rats show a very low level of PPI. We examined the ability of six antipsychotics, given intraperitoneally (i.p.), to reverse this PPI deficit. It was found that clozapine (5-20 mg/kg), olanzapine (5-20 mg/kg) and sertindole (1-10 mg/kg) reversed this deficiency of PPI (i.e. potentiated the low level of PPI). In contrast, risperidone (0.1-1 mg/kg), remoxipride (1-10 mg/kg) and haloperidol (0.1-1 mg/kg) were inactive. The negative results with three clinically active antipsychotics (risperidone, remoxipride and haloperidol) indicate that reversal of this PPI deficit in Wistar rats has poor predictive validity to screen for potential antipsychotic activity. In an attempt to investigate the mechanism that might underlie the reversing effect of clozapine, olanzapine and sertindole, we tested the ability of the alpha 1 adrenoceptor antagonist prazosin (3-20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.01-0.1 mg/kg) and the 5-HT2 antagonist ritanserin (0.3-3 mg/kg) to reverse the PPI deficit. Negative results with these three drugs did not allow us to characterize the receptor(s) that might be implicated in the reversal of this type of PPI deficit.
在之前一项对Sprague-Dawley大鼠的研究中，我们发现，在预脉冲抑制（PPI）实验中，当PPI水平在约10%至40%之间（预脉冲强度比背景噪声高2、9和15分贝）时，抗精神病药物氯氮平和氟哌啶醇，以及α1肾上腺素能受体拮抗剂哌唑嗪，均能有力且剂量依赖性地增强PPI。相比之下，抗精神病药物利培酮、氨磺必利、雷氯必利和瑞莫必利则不能增强PPI。出现假阳性结果（哌唑嗪）以及四个假阴性结果，使我们得出结论，即这种增强PPI的实验作为一种潜在抗精神病药物的筛选工具，其预测效度较低。在本研究中，我们使用了Wistar大鼠，在与Sprague-Dawley大鼠相同的实验方案下，Wistar大鼠表现出极低水平的PPI。我们检测了六种腹腔注射给药的抗精神病药物逆转这种PPI缺陷的能力。结果发现，氯氮平（5 - 20毫克/千克）、奥氮平（5 - 20毫克/千克）和舍吲哚（1 - 10毫克/千克）能逆转这种PPI缺陷（即增强低水平的PPI）。相比之下，利培酮（0.1 - 1毫克/千克）、瑞莫必利（1 - 10毫克/千克）和氟哌啶醇（0.1 - 1毫克/千克）则无此作用。三种临床有效的抗精神病药物（利培酮、瑞莫必利和氟哌啶醇）出现阴性结果，表明在Wistar大鼠中逆转这种PPI缺陷对于筛选潜在抗精神病活性的预测效度较低。为了探究氯氮平、奥氮平和舍吲哚的逆转作用可能潜在的机制，我们检测了α1肾上腺素能受体拮抗剂哌唑嗪（3 - 20毫克/千克）、多巴胺D1受体拮抗剂SCH 23390（0.01 - 0.1毫克/千克）和5 - HT2拮抗剂利坦色林（0.3 - 3毫克/千克）逆转PPI缺陷的能力。这三种药物的阴性结果使我们无法确定可能与这种类型的PPI缺陷逆转有关的受体。
