Effects of the T-type calcium channel antagonist Z944 on paired associates learning and locomotor activity in rats treated with the NMDA receptor antagonist MK-801
Effects of the T-type calcium channel antagonist Z944 on paired associates learning and locomotor activity in rats treated with the NMDA receptor antagonist MK-801
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DOI：
10.1007/s00213-018-5040-3
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发表时间：
2018-11-01
影响因子：
3.4
通讯作者：
Howland, John G.
中科院分区：
文献类型：
--
作者：
Roebuck, Andrew J.;Marks, Wendie N.;Howland, John G.
理由：目前可用的抗精神病药物存在副作用且对精神分裂症认知症状的疗效有限，因此不能令人满意。目前许多可用的药物，例如氟哌啶醇，除了具有公认的多巴胺 D2 受体拮抗作用外，还是 T 型钙通道拮抗剂。因此，对 T 型钙通道拮抗剂/阻滞剂在与精神分裂症相关的行为测定中的作用的临床前研究可能会为新的治疗策略提供信息。 目的我们探讨了最近开发的高选择性 T 型钙通道拮抗剂 Z944（2.5、5.0、10.0 mg/kg）对 MK-801（0.15 mg/kg）急性精神分裂症模型的影响。 方法为了检查 Z944 对精神分裂症相关行为的影响，我们测试了基于触摸屏的配对伙伴学习（考虑到其与疾病认知症状的相关性）和运动活动（考虑到其与阳性症状的相关性）。 结果 Z944 的急性治疗未能逆转 MK-801 在配对伙伴学习中引起的视觉空间联想记忆障碍。单独给予最高剂量的药物（10.0mg/kg）会对配对伙伴的学习产生轻微的损害。相比之下，在运动测定中，Z944 (5.0mg/kg) 阻断了 MK-801 治疗后预期的运动增加。结论这些实验支持 Z944 可能会减少与精神分裂症阳性症状相关的行为，尽管还需要进一步研究其对认知的影响。这些发现和其他研究表明，T 型钙通道拮抗剂可能是目前可用的抗精神病药物的替代品，且副作用较轻。
RationaleCurrently available antipsychotics are unsatisfactory given their side effects and limited efficacy for the cognitive symptoms of schizophrenia. Many currently available drugs, such as haloperidol, are T-type calcium channel antagonists in addition to their well-established antagonism of dopamine D2 receptors. Thus, preclinical research into the effects of T-type calcium channel antagonists/blockers in behavioral assays related to schizophrenia may inform novel therapeutic strategies.ObjectivesWe explored the effects of a recently developed highly selective T-type calcium channel antagonist, Z944 (2.5, 5.0, 10.0mg/kg), on the MK-801 (0.15mg/kg) model of acute psychosis.MethodsTo examine the effects of Z944 on behaviors relevant to schizophrenia, we tested touchscreen-based paired associates learning given its relevance to the cognitive symptoms of the disorder and locomotor activity given its relevance to the positive symptoms.ResultsAcute treatment with Z944 failed to reverse the visuospatial associative memory impairments caused by MK-801 in paired associates learning. The highest dose of drug (10.0mg/kg) given alone produced subtle impairments on paired associates learning. In contrast, Z944 (5.0mg/kg) blocked the expected increase in locomotion following MK-801 treatment in a locomotor assay.ConclusionsThese experiments provide support that Z944 may reduce behaviors relevant to positive symptoms of schizophrenia, although additional study of its effects on cognition is required. These findings and other research suggest T-type calcium channel antagonists may be an alternative to currently available antipsychotics with less serious side effects.