Geyer M A, Krebs-Thomson K, Braff D L, Swerdlow N R
Department of Psychiatry, University of California, San Diego, La Jolla 92093-0804, USA.
Psychopharmacology (Berl). 2001 Jul;156(2-3):117-54. doi: 10.1007/s002130100811.
Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia.
This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats.
Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated.
Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications.
Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.
精神分裂症患者在感觉运动门控的一项操作性指标——惊跳前脉冲抑制（PPI）方面存在缺陷。通过药理学或发育学操作在大鼠中也会产生类似的PPI缺陷。这些在大鼠中实验诱导的PPI缺陷本身显然不是精神分裂症的动物模型，但似乎为精神分裂症患者感觉运动门控缺陷提供了具有表面效度、预测效度和结构效度的模型。在啮齿动物中，惊跳PPI的破坏是由以下因素引起的：苯丙胺或阿扑吗啡刺激D2多巴胺（DA）受体；5-羟色胺（5-HT）释放剂或多种5-羟色胺受体的直接激动剂激活5-羟色胺能系统；苯环利定（PCP）等药物阻断N-甲基-D-天冬氨酸（NMDA）受体。因此，已发展出PPI破坏的多巴胺能、5-羟色胺能和谷氨酸能模型，并已应用于潜在抗精神病药物的鉴定。此外，一些发育学操作，如隔离饲养，提供了精神分裂症中所见PPI缺陷的非药理学动物模型。
本综述总结并评估了评估全身给药对大鼠PPI影响的研究。
汇编了2001年1月15日前研究全身给药对大鼠PPI影响的研究，并整理成六个注释附录。基于该研究目录，对用于抗精神病药物研究的四种主要PPI模型各自的优缺点进行了严格评估。
尽管存在一些明显的不一致之处，但文献有力支持了DA激动剂、5-HT2激动剂、NMDA拮抗剂和隔离饲养在大鼠中引起的PPI显著破坏。这些模型中的每一个对至少一些抗精神病药物都表现出敏感性。虽然基于直接DA激动剂作用的PPI模型在鉴定已知抗精神病药物方面得到了最充分的验证，但隔离饲养模型似乎对典型和非典型抗精神病药物也敏感。5-HT PPI模型对抗精神病药物的总体敏感性较低，但可以深入了解5-羟色胺能系统对作用于多种受体的新型抗精神病药物作用的贡献。NMDA拮抗剂引起的PPI缺陷似乎对氯氮平样非典型抗精神病药物比对典型抗精神病药物更敏感。因此，尽管这一概括存在一些例外情况，但NMDA PPI模型可能有助于鉴定新型或非典型抗精神病药物。
对大鼠PPI药物作用的研究产生了四种独特的模型，这些模型在抗精神病药物的鉴定中具有实用价值。由于这些模型中的每一个都有特定的优缺点，所使用模型的选择取决于所解决的问题。本综述应有助于指导此类决策。
