Smith J W, Fetsko L A, Xu R, Wang Y
Department of Pharmacology, University of Pennsylvania School of Medicine, M102 John Morgan Building, Philadelphia, PA 19014, USA.
Neuroscience. 2002;113(4):755-65. doi: 10.1016/s0306-4522(02)00257-9.
The dopamine D2 receptor (D2) is implicated in drug addiction, learning and memory. Two isoforms of the D2 receptor, termed D2L (long form) and D2S (short form), have been identified. We previously generated mice lacking D2L (D2L-/-), but expressing functional D2S. In this study, we investigated the role of D2L in the positive and negative reinforcing properties of abused drugs and electrical stimuli, using D2L-/- mice as a model system. Mice were trained in three associative learning tasks: conditioned place preference to morphine and cocaine, conditioned place aversion to naloxone-precipitated morphine withdrawal, and active avoidance. D2L-/- mice, like wild type mice, developed a place preference to cocaine. In contrast to wild type mice, D2L-/- mice did not develop a place preference to morphine, nor did they attain a place aversion to morphine withdrawal. D2L-/- mice also failed to acquire avoidance behavior in response to electrical stimuli. There were no significant differences between D2L-/- and wild type mice in mu-opioid receptor density, morphine-induced locomotor stimulation and morphine withdrawal symptoms. These results suggest that D2L may have a greater impact than D2S on the rewarding aspects of morphine, and the aversive properties of morphine withdrawal and electrical stimulus. These findings also suggest that the presence of D2L is critical in the acquisition (learning) and/or retention (memory) of context-stimulus associations in certain situations. On the other hand, D2L is not essential for the rewarding aspects of cocaine and for the development of morphine dependence. Thus, these studies reveal distinct functional roles of D2L and/or D2S in drug addiction and avoidance learning, which may lead to a better understanding of the neurobiological basis underlying these behaviors.
多巴胺D2受体（D2）与药物成瘾、学习和记忆有关。已鉴定出D2受体的两种亚型，即D2L（长亚型）和D2S（短亚型）。我们之前培育出了缺乏D2L（D2L-/-）但表达功能性D2S的小鼠。在本研究中，我们以D2L-/-小鼠为模型系统，研究了D2L在滥用药物和电刺激的正性和负性强化特性中的作用。小鼠接受了三项联想学习任务的训练：对吗啡和可卡因的条件性位置偏爱、对纳洛酮诱发的吗啡戒断的条件性位置厌恶以及主动回避。与野生型小鼠一样，D2L-/-小鼠对可卡因产生了位置偏爱。与野生型小鼠不同的是，D2L-/-小鼠对吗啡没有产生位置偏爱，也没有对吗啡戒断产生位置厌恶。D2L-/-小鼠对电刺激也未能获得回避行为。D2L-/-小鼠和野生型小鼠在μ-阿片受体密度、吗啡诱导的运动兴奋和吗啡戒断症状方面没有显著差异。这些结果表明，D2L可能比D2S对吗啡的奖赏方面、吗啡戒断的厌恶特性和电刺激有更大的影响。这些发现还表明，在某些情况下，D2L的存在对于情境-刺激关联的习得（学习）和/或保留（记忆）至关重要。另一方面，D2L对于可卡因的奖赏方面和吗啡依赖性的发展并非必不可少。因此，这些研究揭示了D2L和/或D2S在药物成瘾和回避学习中的不同功能作用，这可能有助于更好地理解这些行为背后的神经生物学基础。
