Pendyam S, Mohan A, Kalivas P W, Nair S S
Department of Electrical and Computer Engineering, University of Missouri, Columbia, MO 65211, USA.
Neuroscience. 2009 Feb 18;158(4):1266-76. doi: 10.1016/j.neuroscience.2008.11.014. Epub 2008 Nov 18.
Chronic cocaine administration causes instability in extracellular glutamate in the nucleus accumbens that is thought to contribute to the vulnerability to relapse. A computational framework was developed to model glutamate in the extracellular space, including synaptic and nonsynaptic glutamate release, glutamate elimination by glutamate transporters and diffusion, and negative feedback on synaptic release via metabotropic glutamate receptors (mGluR2/3). This framework was used to optimize the geometry of the glial sheath surrounding excitatory synapses, and by inserting physiological values, accounted for known stable extracellular, extrasynaptic concentrations of glutamate measured by microdialysis and glutamatergic tone on mGluR2/3. By using experimental values for cocaine-induced reductions in cystine-glutamate exchange and mGluR2/3 signaling, and by predicting the down-regulation of glutamate transporters, the computational model successfully represented the experimentally observed increase in glutamate that is seen in rats during cocaine-seeking. This model provides a mathematical framework for describing how pharmacological or pathological conditions influence glutamate transmission measured by microdialysis.
长期使用可卡因会导致伏隔核细胞外谷氨酸水平不稳定，这被认为是导致复发易感性的原因之一。我们开发了一个计算框架来模拟细胞外空间中的谷氨酸，包括突触和非突触谷氨酸释放、谷氨酸转运体对谷氨酸的清除和扩散，以及通过代谢型谷氨酸受体（mGluR2/3）对突触释放的负反馈。该框架用于优化围绕兴奋性突触的胶质鞘的几何形状，并通过插入生理值，解释了通过微透析测量的已知稳定的细胞外、突触外谷氨酸浓度以及mGluR2/3上的谷氨酸能张力。通过使用可卡因诱导的胱氨酸-谷氨酸交换和mGluR2/3信号传导减少的实验值，并预测谷氨酸转运体的下调，该计算模型成功地再现了实验观察到的大鼠在寻求可卡因期间谷氨酸增加的现象。该模型提供了一个数学框架，用于描述药理学或病理学条件如何影响通过微透析测量的谷氨酸传递。
