Wilson J M, Nobrega J N, Carroll M E, Niznik H B, Shannak K, Lac S T, Pristupa Z B, Dixon L M, Kish S J
Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, Toronto, Canada.
J Neurosci. 1994 May;14(5 Pt 2):2966-79. doi: 10.1523/JNEUROSCI.14-05-02966.1994.
We examined the influence of chronic cocaine exposure, in an unlimited access self-administration paradigm, on density of the dopamine transporter (3H-WIN 35,428 and 3H-GBR 12,935 binding) and concentration of monoamine (dopamine, serotonin, noradrenaline and metabolites) neurotransmitters in rat brain. In normal rodent striatum 3H-WIN 35,428 and 3H-GBR 12,935 binding to the dopamine transporter, although generally similar, showed different subregional rostrocaudal and mediolateral gradients, suggesting that the two ligands might bind to different subtypes or states of the dopamine transporter. Following chronic, unlimited access cocaine self-administration, binding of 3H-WIN 35,428 was significantly elevated in whole nucleus accumbens (+69%, p < 0.001) and striatum (+65%, p < 0.001) on the last day of cocaine exposure ("on-cocaine group"); whereas in the 3 week withdrawn animals ("cocaine-withdrawn group"), levels were either normal (striatum) or reduced (-30%, p < 0.05, nucleus accumbens). Although similar changes in 3H-GBR 12,935 binding were observed, this dopamine transporter ligand showed a smaller and highly subregionally dependent increase in binding in striatal subdivision of the on-cocaine group, but a more marked binding reduction in the cocaine-withdrawn animals. As compared with the controls, mean dopamine levels were reduced in striatum (-15%, p < 0.05) of the on-cocaine group and in nucleus accumbens (-40%, p < 0.05) of the cocaine-withdrawn group. These data provide additional support to the hypothesis that some of the long-term effects of cocaine exposure (drug craving, depression) could be consequent to reduced nucleus accumbens dopamine function. Our data also suggest that dopamine transporter concentration, and perhaps function, might undergo up- or downregulation, either as a direct effect of cocaine, or indirectly as part of a homeostatic response to altered synaptic dopamine levels, and therefore might participate in the neuronal events underlying cocaine-induced behavioral changes.
我们在无限制获取自我给药范式下，研究了长期接触可卡因对大鼠脑内多巴胺转运体密度（3H-WIN 35,428和3H-GBR 12,935结合）以及单胺（多巴胺、5-羟色胺、去甲肾上腺素及其代谢产物）神经递质浓度的影响。在正常啮齿动物纹状体中，3H-WIN 35,428和3H-GBR 12,935与多巴胺转运体的结合，尽管总体相似，但显示出不同的从嘴尾到头尾以及从内侧到外侧的亚区域梯度，这表明这两种配体可能与多巴胺转运体的不同亚型或状态结合。在长期无限制获取可卡因自我给药后，在可卡因暴露的最后一天（“可卡因给药组”），整个伏隔核（+69%，p < 0.001）和纹状体（+65%，p < 0.001）中3H-WIN 35,428的结合显著升高；而在停药3周的动物（“可卡因戒断组”）中，水平要么正常（纹状体），要么降低（-30%，p < 0.05，伏隔核）。尽管观察到3H-GBR 12,935结合有类似变化，但这种多巴胺转运体配体在可卡因给药组纹状体亚区域的结合增加较小且高度依赖亚区域，而在可卡因戒断动物中结合减少更为明显。与对照组相比，可卡因给药组纹状体中的平均多巴胺水平降低（-15%，p < 0.05），可卡因戒断组伏隔核中的平均多巴胺水平降低（-40%，p < 0.05）。这些数据为以下假说提供了额外支持：可卡因暴露的一些长期影响（药物渴望、抑郁）可能是伏隔核多巴胺功能降低的结果。我们的数据还表明，多巴胺转运体浓度，或许还有功能，可能会经历上调或下调调节，要么是可卡因的直接作用，要么是作为对突触多巴胺水平改变的稳态反应的一部分而间接发生，因此可能参与了可卡因诱导的行为变化背后的神经元事件。
