Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Via Taramelli 14, 27100 Pavia, Italy.
Psychopharmacology (Berl). 2011 Nov;218(1):249-56. doi: 10.1007/s00213-010-2152-9. Epub 2011 Jan 7.
An increasing body of evidence suggests that drug addiction engages circuits also associated with memory processes. In particular, in the hippocampus, a substantial similarity seems to exist between the changes yielded by drugs of abuse and those induced by hippocampal-dependent learning.
Considering the key involvement of neuronal Embryonic Lethal Abnormal Vision (nELAV) proteins in memory processes occurring within the hippocampus and the critical role of stress for compulsive drug use and relapse, we investigated the effect of cocaine and stress challenges on the activation of the nELAV cascade.
Rats were treated subcutaneously with vehicle or cocaine hydrochloride (20 mg/kg, once a day for 2 weeks). Three days later, half of them were also subjected to a single stress exposure. Western blotting and real-time polymerase chain reaction (PCR) experiments were performed on the hippocampi.
Our results show that the combination of repeated exposure to cocaine and acute stress significantly enhances nELAV expression and phosphorylation in the hippocampus with a concomitant increase of GAP43 expression (a specific nELAV target), an effect that seems to involve, upstream, protein kinase C alpha (PKCα). The activation of this pathway occurs independently from widespread neuronal activation since no alterations were observed in the expression of the immediate early gene Arc (a widely established index of neuronal activity), suggesting that the activation of the nELAV-GAP43 cascade reflects a targeting of specific processes rather than a global interference with hippocampal homeostasis.
Based on our results, we speculate that cocaine and stress may recruit such a pathway, crucial for physiological learning, potentially contributing to the aberrant engagement of learning mechanisms observed in drug addiction behavior.
越来越多的证据表明，药物成瘾会涉及到与记忆过程相关的回路。特别是在海马体中，滥用药物引起的变化与海马体依赖性学习引起的变化之间似乎存在着很大的相似性。
考虑到神经元胚胎致死性异常视觉（nELAV）蛋白在海马体中发生的记忆过程中的关键作用，以及应激对于强迫性药物使用和复发的关键作用，我们研究了可卡因和应激挑战对 nELAV 级联激活的影响。
大鼠皮下给予载体或盐酸可卡因（20mg/kg，每天一次，共 2 周）。三天后，其中一半还接受了单次应激暴露。对海马体进行 Western blot 和实时聚合酶链反应（PCR）实验。
我们的结果表明，重复暴露于可卡因和急性应激的组合显著增强了海马体中 nELAV 的表达和磷酸化，同时增加了 GAP43 的表达（nELAV 的特定靶标），这种效应似乎涉及蛋白激酶 Cα（PKCα）。该途径的激活与广泛的神经元激活无关，因为即时早期基因 Arc（神经元活动的广泛确立指标）的表达没有变化，这表明 nELAV-GAP43 级联的激活反映了特定过程的靶向，而不是对海马体平衡的整体干扰。
基于我们的结果，我们推测可卡因和应激可能会招募这样一条通路，该通路对生理学习至关重要，可能有助于药物成瘾行为中观察到的学习机制的异常参与。
