Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Medical School, Atlanta, GA 30332-0535, USA.
Pharmacopsychiatry. 2011 May;44 Suppl 1:S62-75. doi: 10.1055/s-0031-1273707. Epub 2011 May 4.
Major depressive disorder (MDD) affects about 16% of the general population and is a leading cause of death in the United States and around the world. Aggravating the situation is the fact that "drug use disorders" are highly comorbid in MDD patients, and VICE VERSA. Drug use and MDD share a common component, the dopamine system, which is critical in many motivation and reward processes, as well as in the regulation of stress responses in MDD. A potentiating mechanism in drug use disorders appears to be synaptic plasticity, which is regulated by dopamine transmission. In this article, we describe a computational model of the synaptic plasticity of GABAergic medium spiny neurons in the nucleus accumbens, which is critical in the reward system. The model accounts for effects of both dopamine and glutamate transmission. Model simulations show that GABAergic medium spiny neurons tend to respond to dopamine stimuli with synaptic potentiation and to glutamate signals with synaptic depression. Concurrent dopamine and glutamate signals cause various types of synaptic plasticity, depending on input scenarios. Interestingly, the model shows that a single 0.5 mg/kg dose of amphetamine can cause synaptic potentiation for over 2 h, a phenomenon that makes synaptic plasticity of medium spiny neurons behave quasi as a bistable system. The model also identifies mechanisms that could potentially be critical to correcting modifications of synaptic plasticity caused by drugs in MDD patients. An example is the feedback loop between protein kinase A, phosphodiesterase, and the second messenger cAMP in the postsynapse. Since reward mechanisms activated by psychostimulants could be crucial in establishing addiction comorbidity in patients with MDD, this model might become an aid for identifying and targeting specific modules within the reward system and lead to a better understanding and potential treatment of comorbid drug use disorders in MDD.
重度抑郁症（MDD）影响约 16%的普通人群，是美国和全球的主要死亡原因之一。更糟糕的是，“药物使用障碍”在 MDD 患者中高度共病，反之亦然。药物使用和 MDD 共享多巴胺系统这一共同组成部分，该系统在许多动机和奖励过程中以及 MDD 的应激反应调节中至关重要。药物使用障碍中的促进机制似乎是突触可塑性，它受多巴胺传递调节。在本文中，我们描述了一个关于伏隔核中 GABA 能中间神经元突触可塑性的计算模型，该模型对奖励系统至关重要。该模型考虑了多巴胺和谷氨酸传递的影响。模型模拟表明，GABA 能中间神经元倾向于对多巴胺刺激产生突触增强，对谷氨酸信号产生突触抑制。同时存在多巴胺和谷氨酸信号会根据输入情况引起各种类型的突触可塑性。有趣的是，该模型表明，单次 0.5 毫克/千克剂量的安非他命可导致突触增强超过 2 小时，这种现象使中间神经元的突触可塑性表现得几乎像双稳态系统。该模型还确定了可能对纠正 MDD 患者药物引起的突触可塑性改变至关重要的机制。例如，蛋白激酶 A、磷酸二酯酶和突触后第二信使 cAMP 之间的反馈环。由于精神兴奋剂激活的奖励机制可能在确定 MDD 患者共病药物使用障碍方面至关重要，因此该模型可能成为识别和靶向奖励系统内特定模块的辅助手段，并有助于更好地理解和潜在治疗 MDD 中的共病药物使用障碍。
