Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
J Neurophysiol. 2013 Jan;109(1):171-82. doi: 10.1152/jn.00502.2012. Epub 2012 Oct 10.
Dopamine (DA) D2-like autoreceptors are an important component of the DA system, but their influence on postsynaptic DA signaling is not well understood. They are, directly or indirectly, involved in drug abuse and in treatment of schizophrenia and attention deficit hyperactive disorder: DA autoreceptors influence the behavioral effect of cocaine and methylphenidate and may be the target of antipsychotic medications such as haloperidol. DA autoreceptors are active at two levels: Somatodendritic autoreceptors mainly influence firing rate of DA neurons, and presynaptic autoreceptors control release of neurotransmitter at axonal terminals. Here we develop a mathematical model that captures the dynamics of this dual autoregulation system. Our model predicts a biphasic autoreceptor response between DA terminals and somatodendritic regions that influences the postsynaptic integration of DAergic firing patterns. We applied our model to study how DA uptake inhibition affects the translation of DA cell firing into activation of postsynaptic DA receptors. While uptake inhibition increased tonic activation of low-affinity postsynaptic receptors, high-affinity state receptors saturated and thus became insensitive to phasic DA signaling. This effect had remarkable regional specificity: While high-affinity DA receptors saturated at low levels of uptake inhibition in nucleus accumbens, they only saturated at higher levels of uptake inhibition in dorsal striatum. Based on high-affinity receptor saturation, the model predicted that removal of autoreceptor control would lead to cocaine hypersensitivity.
多巴胺（DA）D2 样自身受体是 DA 系统的重要组成部分，但它们对突触后 DA 信号的影响还不太清楚。它们直接或间接地参与了药物滥用以及精神分裂症和注意缺陷多动障碍的治疗：DA 自身受体影响可卡因和哌甲酯的行为效应，并且可能是抗精神病药物（如氟哌啶醇）的作用靶点。DA 自身受体在两个水平上起作用：体树突自身受体主要影响 DA 神经元的发射率，而突触前自身受体控制神经递质在轴突末梢的释放。在这里，我们开发了一个数学模型来捕捉这个双重自身调节系统的动力学。我们的模型预测了 DA 末梢和体树突区域之间的双相自身受体反应，这会影响 DA 能神经元放电模式的突触后整合。我们应用我们的模型来研究 DA 摄取抑制如何将 DA 细胞放电转化为激活突触后 DA 受体。虽然摄取抑制增加了低亲和力突触后受体的紧张性激活，但高亲和力状态受体饱和，因此对相位 DA 信号变得不敏感。这种效应具有显著的区域特异性：虽然在伏隔核中，低水平的摄取抑制就会使高亲和力 DA 受体饱和，但在背侧纹状体中，只有在更高水平的摄取抑制下，高亲和力受体才会饱和。基于高亲和力受体的饱和，该模型预测，去除自身受体控制将导致可卡因敏感性增加。
