Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Eur J Neurosci. 2011 Apr;33(7):1291-8. doi: 10.1111/j.1460-9568.2010.07591.x. Epub 2011 Jan 24.
Relapse is a hallmark of cocaine addiction. Cocaine-induced neuroplastic changes in the mesocorticolimbic circuits critically contribute to this phenomenon. Pre-clinical evidence indicates that relapse to cocaine-seeking behavior depends on activation of dopamine neurons in the ventral tegmental area. Thus, blocking such activation may inhibit relapse. Because the activity of dopamine neurons is regulated by D₂-like autoreceptors expressed on somatodendritic sites, this study, using the reinstatement model, aimed to determine whether activation of D₂-like receptors in the ventral tegmental area can inhibit cocaine-induced reinstatement of extinguished cocaine-seeking behavior. Rats were trained to self-administer i.v. cocaine (0.25 mg/infusion) under a modified fixed-ratio 5 schedule. After such behavior was well learned, rats went through extinction training to extinguish cocaine-seeking behavior. The effect of quinpirole, a selective D₂-like receptor agonist microinjected into the ventral tegmental area, on cocaine-induced reinstatement was then assessed. Quinpirole (0-3.2 μg/side) dose-dependently decreased cocaine-induced reinstatement and such effects were reversed by the selective D₂-like receptor antagonist eticlopride when co-microinjected with quinpirole into the ventral tegmental area. The effect appeared to be specific to the ventral tegmental area because quinpirole microinjected into the substantia nigra had no effect. Because D₂-like receptors are expressed on rat ventral tegmental area dopamine neurons projecting to the pre-frontal cortex and nucleus accumbens, our data suggest that these dopamine circuits may play a critical role in cocaine-induced reinstatement. The role of potential changes in D₂-like receptors and related signaling molecules of dopamine neurons in the vulnerability to relapse was discussed.
复发是可卡因成瘾的一个标志。中脑边缘多巴胺能回路的可卡因诱导神经可塑性变化对此现象有重要贡献。临床前证据表明,可卡因寻求行为的复发取决于腹侧被盖区多巴胺神经元的激活。因此,阻断这种激活可能会抑制复发。由于多巴胺神经元的活动受表达在躯体树突部位的 D₂样自身受体调节,因此,本研究使用复吸模型旨在确定腹侧被盖区 D₂样受体的激活是否可以抑制可卡因诱导的已消除可卡因寻求行为的复吸。大鼠接受训练以静脉内自我给药(0.25mg/ 输注),采用改良的固定比率 5 方案。在这种行为得到很好的学习后,大鼠进行了消退训练以消除可卡因寻求行为。然后评估了选择性 D₂样受体激动剂喹吡罗(quinpirole)微注射到腹侧被盖区对可卡因诱导的复吸的影响。喹吡罗(0-3.2μg/ 侧)剂量依赖性地降低了可卡因诱导的复吸,并且当与喹吡罗共同微注射到腹侧被盖区时,选择性 D₂样受体拮抗剂 eticlopride 逆转了这种作用。这种作用似乎是特异性的,因为喹吡罗微注射到黑质没有效果。由于 D₂样受体表达在投射到前额叶皮层和伏隔核的大鼠腹侧被盖区多巴胺神经元上,我们的数据表明,这些多巴胺回路可能在可卡因诱导的复吸中起关键作用。讨论了多巴胺神经元中 D₂样受体和相关信号分子的潜在变化在易复发中的作用。