Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
Nat Neurosci. 2011 Jul 10;14(8):1033-8. doi: 10.1038/nn.2862.
Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.
多巴胺（DA）神经元中表达的 D2 受体（D2 自身受体）发挥负反馈调节作用，降低 DA 神经元的放电、DA 的合成和释放。由于 D2 受体主要在突触后神经元中表达，药理学和遗传学方法都无法明确确定 D2 自身受体对 DA 介导的行为的体内贡献。我们发现，缺乏 D2 自身受体（Drd2(loxP/loxP); Dat(+/IRES-cre)，称为 autoDrd2KO 小鼠）的中脑 DA 神经元缺乏 DA 介导的树突体突触反应和 DA 释放的抑制。AutoDrd2KO 小鼠表现出升高的 DA 合成和释放、过度活跃以及对可卡因的精神运动效应的超敏反应。这些小鼠还表现出对可卡因的更高的位置偏好和对食物奖励的更高动机。我们的结果强调了 D2 自身受体在 DA 神经传递调节中的重要性，并表明 D2 自身受体对于正常的运动功能、觅食行为以及对可卡因的运动和奖励特性的敏感性很重要。
