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多巴胺受体缺陷小鼠中增强的潜伏抑制对D1受体亚型具有性别特异性,对D2受体亚型则不然:对抗精神病药物作用的启示。

Enhanced latent inhibition in dopamine receptor-deficient mice is sex-specific for the D1 but not D2 receptor subtype: implications for antipsychotic drug action.

作者信息

Bay-Richter Cecilie, O'Tuathaigh Colm M P, O'Sullivan Gerard, Heery David M, Waddington John L, Moran Paula M

机构信息

School of Psychology, University of Nottingham, Nottingham, UK.

出版信息

Int J Neuropsychopharmacol. 2009 Apr;12(3):403-14. doi: 10.1017/S1461145708009656. Epub 2008 Nov 17.

Abstract

Latent inhibition (LI) is reduced learning to a stimulus that has previously been experienced without consequence. It is an important model of abnormal allocation of salience to irrelevant information in patients with schizophrenia. In rodents LI is abolished by psychotomimetic drugs and in experimental conditions where LI is low in controls, its expression is enhanced by antipsychotic drugs with activity at dopamine (DA) receptors. It is however unclear what the independent contributions of DA receptor subtypes are to these effects. This study therefore examined LI in congenic DA D1 and D2 receptor knockout (D1 KO and D2 KO) mice. Conditioned suppression of drinking was used as the measure of learning in the LI procedure. Both male and female DA D2 KO mice showed clear enhancement of LI reproducing antipsychotic drug effects in the model. Unexpectedly, enhancement was also seen in D1 KO female mice but not in D1 KO male mice. This sex-specific pattern was not replicated in locomotor or motor coordination tasks nor in the effect of DA KOs on baseline learning in control groups indicating some specificity of the effect to LI. These data suggest that the dopaminergic mechanism underlying LI potentiation and possibly antipsychotic action may differ between the sexes, being mediated by D2 receptors in males but by both D1 and D2 receptors in females. These data suggest that the DA D1 receptor may prove an important target for understanding sex differences in the mechanisms of action of antipsychotic drugs and in the aetiology of aberrant salience allocation in schizophrenia.

摘要

潜伏抑制(LI)是指对先前曾无结果地经历过的刺激的学习能力下降。它是精神分裂症患者将显著性异常分配到无关信息的一个重要模型。在啮齿动物中,拟精神病药物可消除LI,在对照组中LI较低的实验条件下,具有多巴胺(DA)受体活性的抗精神病药物可增强其表达。然而,尚不清楚DA受体亚型对这些效应的独立贡献是什么。因此,本研究检测了同基因DA D1和D2受体敲除(D1 KO和D2 KO)小鼠的LI。在LI程序中,采用条件性饮水抑制作为学习的测量指标。雄性和雌性DA D2 KO小鼠均表现出LI明显增强,重现了该模型中的抗精神病药物效应。出乎意料的是,D1 KO雌性小鼠也出现了增强,但D1 KO雄性小鼠未出现。这种性别特异性模式在运动或运动协调任务中未重现,DA敲除对对照组基线学习也无影响,表明该效应对LI具有一定特异性。这些数据表明,LI增强以及可能的抗精神病作用的多巴胺能机制在性别之间可能存在差异,在雄性中由D2受体介导,而在雌性中由D1和D2受体共同介导。这些数据表明,DA D1受体可能是理解抗精神病药物作用机制中的性别差异以及精神分裂症中异常显著性分配病因学的一个重要靶点。

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