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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats.
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Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats.

机译：在维斯塔大鼠亚慢性地佐西平或苯环利定治疗后，氯氮平可增强对前脉冲抑制的破坏。

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Sensitisation (i.e. progressive enhancement) of behavioural abnormalities induced by repeated treatment with non-competitive NMDA receptor antagonists in animals is considered an animal model for schizophrenia. Here, male Wistar rats were treated for 11 days with either dizocilpine (0.1 mg/kg), phencyclidine (PCP, 2 mg/kg), or saline and tested for prepulse inhibition (PPI) of the acoustic startle response (ASR). The aims of this study were twofold: First, we tested whether sensitisation of PPI deficits previously found in Sprague-Dawley rats were also found in Wistar rats, and, second, whether these effects can be ameliorated by the atypical antipsychotic clozapine. PPI is a paradigm for the assessment of sensorimotor gating (and its deficits) and is impaired in schizophrenic patients. After the sub-chronic treatment the rats were tested drug-free (day 12), and on the following days after drug challenge by PCP (2 mg/kg), combinations of PCP (2 mg/kg) and clozapine (5 and 10 mg/kg), or clozapine (5 mg/kg) alone. PPI was significantly reduced by both NMDA receptor antagonists. This effect was not further enhanced by the daily treatment. Startle magnitude was increased after eight days of dizocilpine-treatment only, indicating sensitisation of startle-potentiation by this drug. Testing the rats drug-free on day 12 revealed enhanced PPI and reduced startle (compared to the matching test on day 0) irrespective of previous treatment. Drug challenge with PCP (2 mg/kg) again reduced PPI in all groups. Clozapine (5 and 10 mg/kg) failed to antagonise the PPI-disruptive effects of PCP and even enhanced the PCP-induced PPI-deficits in rats pretreated with PCP or dizocilpine. These findings suggest: (1) that PPI and startle are influenced differently by non-competitive NMDA receptor antagonists, (2) that PCP and dizocilpine reduce PPI in Wistar rats, but do not lead to a sensitisation of this effect; and (3) that under the present schedule of treatments, the antipsychotic compound clozapine does not antagonise but rather enhances PPI-disruptive effects of non-competitive NMDA receptor antagonists, pointing towards a complex interaction of the brain processes underlying the action of psychotomimetic and atypical antipsychotic drugs.
机译：通过用非竞争性NMDA受体拮抗剂反复治疗动物引起的行为异常的敏化（即进行性增强）被认为是精神分裂症的动物模型。在这里，雄性Wistar大鼠用地佐西平（0.1 mg / kg），苯环利定（PCP，2 mg / kg）或生理盐水处理11天，并测试了惊吓反应（ASR）的脉冲前抑制（PPI）。这项研究的目的是双重的：首先，我们测试了在Wistar大鼠中是否也发现了以前在Sprague-Dawley大鼠中发现的PPI缺乏症的致敏性;其次，非典型的抗精神病药物氯氮平是否可以改善这些效应。 PPI是评估感觉运动门控（及其缺陷）的范例，在精神分裂症患者中受损。亚慢性治疗后，对大鼠进行无药测试（第12天），并在用PCP（2 mg / kg），PCP（2 mg / kg）和氯氮平（5和10）联合用药攻击后的第二天毫克/公斤）或氯氮平（5毫克/公斤）。两种NMDA受体拮抗剂均显着降低PPI。日常治疗并未进一步增强这种效果。仅在二唑西平治疗八天后，惊吓程度才增加，表明该药使惊吓增强致敏。与第0天的匹配测试相比，在第12天对大鼠进行了无药测试，结果显示PPI增强，惊吓减少（与第0天的匹配测试相比）。 PCP（2 mg / kg）激发的药物再次降低了所有组的PPI。氯氮平（5和10 mg / kg）不能拮抗PCP的PPI破坏作用，甚至不能增强PCP或地佐西平预处理的大鼠中PCP诱导的PPI缺陷。这些发现表明：（1）非竞争性NMDA受体拮抗剂对PPI和惊吓的影响不同;（2）PCP和地佐西平会降低Wistar大鼠的PPI，但不会导致这种作用的敏化; （3）在目前的治疗方案下，抗精神病药物氯氮平不会拮抗而是增强非竞争性NMDA受体拮抗剂的PPI破坏作用，这表明拟精神病药物和非典型药物作用的大脑过程之间存在复杂的相互作用。抗精神病药。

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