ANTIPSYCHOTIC AGENTS ANTAGONIZE NONCOMPETITIVE N-METHYL-D-ASPARTATE ANTAGONIST-INDUCED BEHAVIORS
ANTIPSYCHOTIC AGENTS ANTAGONIZE NONCOMPETITIVE N-METHYL-D-ASPARTATE ANTAGONIST-INDUCED BEHAVIORS
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DOI：
10.1007/bf02246146
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发表时间：
1995-07-01
影响因子：
3.4
通讯作者：
DUNN, RW
中科院分区：
文献类型：
--
作者：
CORBETT, R;CAMACHO, F;DUNN, RW
测试抗精神病药物拮抗多巴胺能诱导的和非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂诱导的行为的能力。所有药物均剂量依赖性拮抗阿扑吗啡诱导的小鼠攀爬试验（CMA）和地佐环平（MK-801）诱导的运动和跌倒试验（MK-801-LF），CMA/MK-801-LF比值小于或等于1.6。然而，氯氮平及其结构类似物奥氮平对MK-801-LF的拮抗作用（1.1和0.05 mg/kg）强于CMA（12.3和0.45 mg/kg），因此CMA/MK-801-LF比值分别为11.2和9。此外，苯环利定（PCP）（2 mg/kg）可以选择性地诱导幼稚大鼠的社会退缩，这些大鼠在测试前成对（熟悉）饲养10天，而不影响运动活动。SCH 23390、雷氯必利、氟哌啶醇、氯丙嗪和利培酮未能逆转PCP诱导的社交退缩，直至剂量达到产生显著运动损伤的剂量。然而，氯氮平（2.5和5.0毫克/公斤）和奥氮平（0.25和0.5毫克/公斤）显着逆转这种社会退缩的大鼠。因此，非竞争性NMDA拮抗剂PCP和MK-801可诱导啮齿动物的行为，而氯氮平和奥氮平可选择性拮抗PCP和MK-801诱导的行为。此外，在CMA、MK-801-LF和PCP诱导的社交戒断试验中评估抗精神病药物的作用可能提供一种临床前方法，以确定治疗阴性症状和难治性精神分裂症的新型药物。
Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.