Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
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DOI：
10.1046/j.0953-816x.2001.01842.x
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发表时间：
2002-01-01
影响因子：
3.4
通讯作者：
Rubinstein, M
中科院分区：
文献类型：
--
作者：
Falzone, TL;Gelman, DM;Rubinstein, M
前额叶皮层从腹侧被盖区接收主要的多巴胺能输入，腹侧被盖区在影响对应激环境刺激的行为反应的神经元信号的整合中起重要作用。多巴胺D4受体（D4 R）在前额叶皮层中以最高水平表达，并且是定位于该脑区的主要D2样受体。为了研究D4 Rs在多巴胺介导的反应中的功能意义，我们分析了缺乏这种受体亚型（Drd 4（-/-））的小鼠品系。野生型和Drd 4（-/-）小鼠在两种不同的接近/回避冲突范例中受到攻击：高架十字迷宫和亮/暗偏好探索测试。通过这些行为测量，Drd 4（-/-）小鼠显示出对每个迷宫的更引起恐惧的区域的回避增加，如通过减少探索正迷宫的开放臂和延长探索明/暗穿梭箱的照明隔室的潜伏期所证明的。这些夸张的回避行为进一步加强了额外的处理压力，但完全防止抗焦虑药，如苯二氮卓类咪达唑仑和乙醇。尽管Drd 4（-/-）小鼠表现出高度的焦虑，但它们在两瓶选择测试中表现出正常的乙醇偏好和消费。通过情境、线索和工具性恐惧条件反射测试评估的习得性恐惧反应显示野生型和Drd 4（-/-）小鼠之间没有差异。综上所述，这些结果表明，D4 R的缺乏增加了回避行为的无条件刺激，并不损害行为反应巴甫洛夫恐惧条件反射，这表明D4 R可能发挥关键作用，多巴胺能调节皮质信号触发的环境刺激。
The prefrontal cortex receives a major dopaminergic input from the ventral tegmental area, which plays an important role in the integration of neuronal signals influencing behavioural responses to stressful environmental stimuli, The dopamine D4 receptor (D4R) is expressed at highest levels in the prefrontal cortex and is the predominant D2-like receptor localized in this brain area. To investigate the functional significance of D4Rs in dopamine-mediated responses we have analysed a strain of mice lacking this receptor subtype (Drd4(-/-)). Wild-type and Drd4(-/-) mice were challenged in two different approach/avoidance conflict paradigms: the elevated plus maze and the light/dark preference exploration test. By these behavioural measures Drd4(-/-) mice showed heightened avoidance to the more fear-provoking areas of each maze as demonstrated by reduced exploration of the open arms of the plus maze and longer latencies to explore the illuminated compartment of the light/dark shuttle box. These exaggerated avoidance behaviours were further enhanced by an additional handling stress but completely prevented by anxiolytic agents such as the benzodiazepine midazolam and ethanol. Although Drd4(-/-) mice displayed heightened anxiety, they exhibited normal ethanol preference and consumption in a two-bottle choice test. Learned fear responses evaluated by contextual, cued and instrumental fear-conditioning tests showed no difference between wild-type and Drd4(-/-) mice. Taken together these results indicate that the absence of D4Rs increases avoidance behaviour to unconditioned stimuli and does not impair behavioural reactions to Pavlovian fear-conditioning, suggesting that the D4R could play a key role in the dopaminergic modulation of cortical signals triggered by environmental stimuli.