D-Amphetamine and Antipsychotic Drug Effects on Latent Inhibition in Mice Lacking Dopamine D2 Receptors
D-Amphetamine and Antipsychotic Drug Effects on Latent Inhibition in Mice Lacking Dopamine D2 Receptors
复制标题
DOI：
10.1038/npp.2013.50
复制
发表时间：
2013-07-01
影响因子：
7.6
通讯作者：
Moran, P. M.
中科院分区：
文献类型：
--
作者：
Bay-Richter, C.;O'Callaghan, M. J.;Moran, P. M.
诱发精神病的药物，如D-安非他明（AMP），以及缓解精神病的药物，如抗精神病药物，被认为通过多巴胺受体D-2（D-2）发挥行为作用。所有抗精神病药物都是D-2拮抗剂，但D-2拮抗作用是这些药物严重和使人衰弱的副作用的基础;因此，了解D-2是否是其行为效应所必需的是很重要的。使用D-2缺失小鼠（Drd（2）-/-），我们首先研究了AMP破坏潜伏抑制（LI）是否需要D-2。LI是一个学习忽略无关刺激的过程。AMP模型对LI的破坏损害了注意力和异常的显著性分配，从而导致与精神分裂症相关的多巴胺失调。在野生型（WT）和Drd（2）-/-中均观察到LI的AMP破坏。这与AMP诱导的运动过度活跃形成对比，其在Drd（2）-/-中减少。多巴胺受体D-1（Drd（1）-/-）缺失的小鼠，AMP对LI的破坏减弱，表明D1可能在AMP对LI的破坏中起作用。进一步支持这种可能性，我们发现，D1拮抗剂SKF 83566衰减AMP破坏野生型LI。值得注意的是，氟哌啶醇和氯氮平都减弱了Drd（2）-/-中LI的AMP破坏。这表明，抗精神病药物可以减弱AMP在缺乏D-2受体的情况下对学习忽略无关刺激的干扰。数据表明，D-2是不是必不可少的，无论是AMP破坏或抗精神病药物逆转AMP中断学习忽略无关的刺激，并进一步认为D-1值得调查在调解AMP中断这些过程。
Drugs that induce psychosis, such as D-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D-2 (D-2). All antipsychotic drugs are D-2 antagonists, but D-2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D-2 is necessary for their behavioral effects. Using D-2-null mice (Drd(2)-/-), we first investigated whether D-2 is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and Drd(2)-/-. This was in contrast to AMP-induced locomotor hyperactivity, which was reduced in Drd(2)-/-. AMP disruption of LI was attenuated in mice lacking dopamine receptor D-1 (Drd(1)-/-), suggesting that D1 may play a role in AMP disruption of LI. Further supporting this possibility, we found that D1 antagonist SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in Drd(2)-/-. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D-2 receptors. Data suggest that D-2 is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D-1 merits investigation in the mediation of AMP disruption of these processes.