Division of Neurodegeneration, Florey Neuroscience Institutes, University of Melbourne, Parkville, VIC 3010, Australia.
Neuroscience. 2011 Feb 3;174:143-50. doi: 10.1016/j.neuroscience.2010.11.055. Epub 2010 Dec 1.
Drug addiction is associated with altered dopamine (DA) neurotransmission in the basal ganglia. We have previously shown that chronic stimulation of the dopamine D2 receptor (D(2)R) with cocaine results in reduced striatal DA terminal density. The aims of this study were to establish whether this reduction in DA terminal density results in reduced striatal DA release and increased cocaine-seeking behaviour and whether D(2)R antagonism can restore the cocaine-induced alterations in DA neurotransmission and drug-seeking behaviour. Rats were housed individually and either control, cocaine, haloperidol (D(2)R antagonist), or cocaine and haloperidol was administered in the drinking water for 16 weeks. Chronic cocaine treatment, which reduced striatal DA terminal density by 20%, resulted in a reduction in basal (-34%) and cocaine-evoked (-33%) striatal DA release and increased cocaine-seeking behaviour. These cocaine-mediated effects on striatal DA terminal density, DA release and drug-seeking could be prevented by co-administration with haloperidol. Basal and cocaine-evoked DA release in the striatum directly correlated with DA terminal density and with preference for cocaine. We conclude that striatal DA terminal density and DA release is an important factor in maintaining drug preference and should be considered as a factor in drug-seeking behaviour and relapse.
药物成瘾与基底神经节中多巴胺（DA）神经递质传递的改变有关。我们之前已经表明，可卡因对多巴胺 D2 受体（D2R）的慢性刺激会导致纹状体 DA 末梢密度降低。本研究的目的是确定这种 DA 末梢密度的降低是否会导致纹状体 DA 释放减少和可卡因寻求行为增加，以及 D2R 拮抗是否可以恢复可卡因引起的 DA 神经传递和药物寻求行为的改变。大鼠单独饲养，并在饮用水中给予对照、可卡因、氟哌啶醇（D2R 拮抗剂）或可卡因和氟哌啶醇 16 周。慢性可卡因处理使纹状体 DA 末梢密度降低了 20%，导致基础（-34%）和可卡因诱发的（-33%）纹状体 DA 释放减少，并增加了可卡因寻求行为。氟哌啶醇的共同给药可以预防这些可卡因对纹状体 DA 末梢密度、DA 释放和药物寻求的影响。纹状体中基础和可卡因诱发的 DA 释放与 DA 末梢密度和可卡因偏好直接相关。我们得出结论，纹状体 DA 末梢密度和 DA 释放是维持药物偏好的重要因素，应被视为药物寻求行为和复发的一个因素。
