Linn Gary S, Negi Shobhit S, Gerum Scott V, Javitt Daniel C
The Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Psychopharmacology (Berl). 2003 Sep;169(3-4):234-9. doi: 10.1007/s00213-003-1533-8. Epub 2003 Jul 4.
Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating, which occurs across species and is deficient in severe neuropsychiatric disorders such as schizophrenia. In monkeys, as in rodents, phencyclidine (PCP) induces schizophrenia-like deficits in PPI. In rodents, in general, typical antipsychotics (e.g. haloperidol) reverse PPI deficits induced by dopamine (DA) agonists (e.g. apomorphine), but not those induced by N-methyl- d-aspartate (NMDA) receptor antagonists [e.g. phencyclidine (PCP)], whereas atypical antipsychotics (e.g. clozapine) reverse PPI deficits induced by DA agonists and NMDA antagonists. However, some discrepancies exist with some compounds and strains of rodents.
This study investigated whether a typical (haloperidol, 0.035 mg/kg) and an atypical (clozapine, 2.5 mg/kg) antipsychotic could be distinguished in their ability to reverse PCP-induced deficits in PPI in eight monkeys ( Cebus apella).
First, haloperidol dose was determined by its ability to attenuate apomorphine-induced deficits in PPI. Then, haloperidol and clozapine were tested in eight monkeys with PCP-induced deficits of PPI. Experimental parameters were similar to standard human PPI procedures, with 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse 16 dB above the 70 dB background noise.
Clozapine reversed PCP-induced PPI deficits. In contrast, haloperidol did not significantly attenuate PCP-induced PPI deficits even at doses that significantly attenuated apomorphine effects.
In this primate model, clozapine was distinguishable from haloperidol by its ability to attenuate PCP-induced deficits in PPI. The results provide further evidence that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.
听觉惊吓反射的前脉冲抑制（PPI）是一种感觉运动门控的测量指标，它在物种间普遍存在，并且在精神分裂症等严重神经精神疾病中存在缺陷。在猴子中，与啮齿动物一样，苯环己哌啶（PCP）会导致PPI出现类似精神分裂症的缺陷。一般来说，在啮齿动物中，典型抗精神病药物（如氟哌啶醇）可逆转多巴胺（DA）激动剂（如阿扑吗啡）诱导的PPI缺陷，但不能逆转N-甲基-D-天冬氨酸（NMDA）受体拮抗剂[如苯环己哌啶（PCP）]诱导的缺陷，而非典型抗精神病药物（如氯氮平）可逆转DA激动剂和NMDA拮抗剂诱导的PPI缺陷。然而，在一些化合物和啮齿动物品系中存在一些差异。
本研究调查了在八只僧帽猴（Cebus apella）中，典型抗精神病药物（氟哌啶醇，0.035mg/kg）和非典型抗精神病药物（氯氮平，2.5mg/kg）在逆转PCP诱导的PPI缺陷方面的能力是否存在差异。
首先，根据氟哌啶醇减轻阿扑吗啡诱导的PPI缺陷的能力来确定其剂量。然后，在八只出现PCP诱导的PPI缺陷的猴子中测试氟哌啶醇和氯氮平。实验参数与标准的人类PPI程序相似，使用115dB的白噪声惊吓脉冲，单独呈现或在其前120ms呈现一个比70dB背景噪声高16dB的前脉冲。
氯氮平逆转了PCP诱导的PPI缺陷。相比之下，即使在能显著减轻阿扑吗啡效应的剂量下，氟哌啶醇也未显著减轻PCP诱导的PPI缺陷。
在这个灵长类动物模型中，氯氮平通过减轻PCP诱导的PPI缺陷的能力与氟哌啶醇区分开来。这些结果进一步证明，非人类灵长类动物的PPI可能为新型抗精神分裂症药物的开发提供一个重要的动物模型。
