Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology and Institute for Neuroscience, University of Texas at Austin, Austin, Texas 78712, USA.
J Neurosci. 2010 May 12;30(19):6689-99. doi: 10.1523/JNEUROSCI.4453-09.2010.
Synaptic plasticity in the mesolimbic dopamine (DA) system is critically involved in reward-based conditioning and the development of drug addiction. Ca2+ signals triggered by postsynaptic action potentials (APs) drive the induction of synaptic plasticity in the CNS. However, it is not clear how AP-evoked Ca2+ signals and the resulting synaptic plasticity are altered during in vivo exposure to drugs of abuse. We have recently described long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated transmission onto DA neurons that is induced in a manner dependent on bursts of APs. LTP induction requires amplification of burst-evoked Ca2+ signals by preceding activation of metabotropic glutamate receptors (mGluRs) generating inositol 1,4,5-trisphosphate (IP3). In this study, using brain slices prepared from male rats, we show that repeated in vivo exposure to the psychostimulant amphetamine (5 mg/kg, i.p., 3-7 d) upregulates mGluR-dependent facilitation of burst-evoked Ca2+ signals in DA neurons of the ventral tegmental area (VTA). Protein kinase A (PKA)-induced sensitization of IP3 receptors mediates this upregulation of mGluR action. As a consequence, NMDAR-mediated transmission becomes more susceptible to LTP induction after repeated amphetamine exposure. We have also found that the magnitude of amphetamine-conditioned place preference (CPP) in behaving rats correlates with the magnitude of mGluR-dependent Ca2+ signal facilitation measured in VTA slices prepared from these rats. Furthermore, the development of amphetamine CPP is significantly attenuated by intra-VTA infusion of the PKA inhibitor H89. We propose that enhancement of mGluR-dependent NMDAR plasticity in the VTA may promote the learning of environmental stimuli repeatedly associated with amphetamine experience.
中脑边缘多巴胺（DA）系统中的突触可塑性对于基于奖励的条件作用和药物成瘾的发展至关重要。突触后动作电位（AP）引发的 Ca2+信号驱动中枢神经系统中突触可塑性的诱导。然而，在体内暴露于滥用药物期间，AP 引发的 Ca2+信号和由此产生的突触可塑性如何改变尚不清楚。我们最近描述了一种 NMDA 受体（NMDAR）介导的传入到 DA 神经元的长时程增强（LTP），其诱导方式依赖于 AP 的爆发。LTP 的诱导需要通过先前激活代谢型谷氨酸受体（mGluRs）来放大爆发引发的 Ca2+信号，从而产生肌醇 1,4,5-三磷酸（IP3）。在这项研究中，我们使用从雄性大鼠中制备的脑切片表明，重复的体内暴露于精神兴奋剂安非他命（5mg/kg，ip，3-7d）会增加腹侧被盖区（VTA）DA 神经元中 mGluR 依赖性的爆发引发的 Ca2+信号的易化。蛋白激酶 A（PKA）诱导的 IP3 受体敏化介导了 mGluR 作用的这种上调。结果，NMDAR 介导的传递在重复安非他命暴露后更容易受到 LTP 诱导。我们还发现，在行为大鼠中安非他命条件性位置偏好（CPP）的幅度与从这些大鼠中制备的 VTA 切片中测量的 mGluR 依赖性 Ca2+信号易化的幅度相关。此外，VTA 内注射 PKA 抑制剂 H89 可显著减弱安非他命 CPP 的发展。我们提出，VTA 中 mGluR 依赖性 NMDAR 可塑性的增强可能促进与安非他命经历反复相关的环境刺激的学习。
