Williams Jason M, Steketee Jeffery D
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Synapse. 2005 Feb;55(2):98-109. doi: 10.1002/syn.20093.
Previous data suggest that cocaine-induced dopamine (DA) transmission within the medial prefrontal cortex (mPFC) undergoes time-dependent changes during withdrawal from repeated cocaine administration. The current studies assessed two potential mechanisms that may underlie this neuroadaptation. One set of experiments examined alterations in DA clearance in the mPFC of rats that had been pretreated with four administrations of cocaine (15 mg/kg, i.p.; once per day for 4 days) and were withdrawn 1, 7, or 30 days. No significant changes in mPFC DA uptake into crude mPFC synaptosomes or in mPFC DA transporter levels were observed at any of the time points examined. Uptake assay and Western blotting sensitivity was confirmed with prefrontal 6-hydroxydopamine lesions, which significantly reduced [3H]DA uptake and DA transporter immunoreactivity in mPFC synaptosomes. To evaluate temporal changes in DA release resulting from repeated cocaine, additional experiments utilized in vivo microdialysis to locally infuse KCl (10, 30, or 100 mM) into the mPFC over the same withdrawal time course used in the uptake studies. After 1-7 days of withdrawal, KCl-stimulated DA release was significantly reduced in the mPFC of cocaine-pretreated animals. However, after 30 days of withdrawal the evoked release of DA in the mPFC of saline- and cocaine-pretreated animals was similar. These data suggest that previously reported modulation of cocaine-induced mPFC DA transmission occurring upon withdrawal from repeated cocaine might arise from transient changes in DA releasability rather than clearance. The relevance of these findings is discussed in relation to mPFC involvement in psychostimulant sensitization.
先前的数据表明，在从重复给予可卡因的戒断过程中，内侧前额叶皮质（mPFC）内可卡因诱导的多巴胺（DA）传递会发生时间依赖性变化。当前的研究评估了可能是这种神经适应性基础的两种潜在机制。一组实验检测了经四次给予可卡因（15毫克/千克，腹腔注射；每天一次，共4天）预处理并在戒断1、7或30天的大鼠mPFC中DA清除的改变。在所检测的任何时间点，均未观察到mPFC中粗制mPFC突触体对DA的摄取或mPFC中DA转运体水平有显著变化。用前额叶6-羟基多巴胺损伤证实了摄取测定和蛋白质印迹的敏感性，该损伤显著降低了mPFC突触体中[3H]DA摄取和DA转运体免疫反应性。为了评估重复给予可卡因导致的DA释放的时间变化，另外的实验在与摄取研究相同的戒断时间过程中，利用体内微透析将氯化钾（10、30或100毫摩尔）局部注入mPFC。在戒断1至7天后，可卡因预处理动物的mPFC中氯化钾刺激的DA释放显著减少。然而，在戒断30天后，生理盐水和可卡因预处理动物的mPFC中诱发的DA释放相似。这些数据表明，先前报道的从重复给予可卡因戒断时发生的可卡因诱导的mPFC DA传递调节可能源于DA释放能力的短暂变化而非清除。结合mPFC参与精神兴奋剂敏化讨论了这些发现的相关性。
