Taylor Jane R, Lynch Wendy J, Sanchez Hayde, Olausson Peter, Nestler Eric J, Bibb James A
Department of Psychiatry, Division of Molecular Psychiatry and Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06508, USA.
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4147-52. doi: 10.1073/pnas.0610288104. Epub 2007 Feb 23.
Neuronal adaptations in striatal dopamine signaling have been implicated in enhanced responses to addictive drugs. Cyclin-dependent kinase 5 (Cdk5) regulates striatal dopamine signaling and is a downstream target gene of the transcription factor DeltaFosB, which accumulates in striatal neurons after chronic cocaine exposure. Here we investigated the role of Cdk5 activity in the nucleus accumbens (NAc) on cocaine-induced locomotor sensitization, responding for reward-associated stimuli (conditioned reinforcement), and cocaine self-administration under a progressive ratio schedule. Repeated infusions of the Cdk5 inhibitor roscovitine into the NAc before cocaine injections augmented both the development and expression of cocaine sensitization without having any intrinsic stimulant actions of its own. Additionally, repeated intra-NAc infusions of roscovitine to saline-injected rats enhanced locomotor responses to a subsequent cocaine challenge. Similar effects were found after infusions of another Cdk5 inhibitor, olomoucine, but not its inactive congener, iso-olomoucine. Repeated inhibition of Cdk5 within the NAc also robustly enhanced the incentive-motivational effects of cocaine, similar to the effect of prior repeated cocaine exposure. The enhanced responding with conditioned reinforcement induced by cocaine persisted at least 2 weeks after the final roscovitine infusion. NAc infusions of olomoucine also produced acute and enduring increases in "breakpoints" achieved on a progressive ratio schedule for cocaine reinforcement. These results demonstrate profound and persistent effects of NAc Cdk5 inhibition on locomotor sensitization and incentive-motivational processes and provide direct evidence for a role for striatal Cdk5-induced alterations in the brain's long-term adaptations to cocaine.
纹状体多巴胺信号通路中的神经元适应性变化与对成瘾性药物的反应增强有关。细胞周期蛋白依赖性激酶5（Cdk5）调节纹状体多巴胺信号通路，并且是转录因子DeltaFosB的下游靶基因，DeltaFosB在慢性可卡因暴露后在纹状体神经元中积累。在此，我们研究了伏隔核（NAc）中Cdk5活性对可卡因诱导的运动致敏、对奖赏相关刺激的反应（条件性强化）以及在累进比率程序下可卡因自我给药的作用。在注射可卡因之前，向NAc重复输注Cdk5抑制剂roscovitine，可增强可卡因致敏的发展和表达，而其自身没有任何内在的刺激作用。此外，向注射生理盐水的大鼠NAc重复输注roscovitine，可增强其对随后可卡因激发的运动反应。在输注另一种Cdk5抑制剂olomoucine后也发现了类似的效果，但输注其无活性的同系物异olomoucine则没有。NAc内Cdk5的重复抑制也强烈增强了可卡因的激励动机作用，类似于先前重复可卡因暴露的效果。由可卡因诱导的条件性强化增强反应在最后一次输注roscovitine后至少持续2周。向NAc输注olomoucine也使可卡因强化的累进比率程序中达到的“断点”产生急性和持久的增加。这些结果证明了NAc中Cdk5抑制对运动致敏和激励动机过程具有深刻而持久的影响，并为纹状体Cdk5诱导的大脑对可卡因长期适应性改变的作用提供了直接证据。
