Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Learn Mem. 2014 Feb 18;21(3):153-60. doi: 10.1101/lm.032292.113.
The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG.
海马齿状回（DG）对于空间记忆至关重要，并且被认为与药物相关的联想记忆的形成有关。在这里，我们试图通过研究连续暴露于尼古丁和可卡因对 DG 中的长期突触增强（LTP）的影响来检验 Gateway Hypothesis 的一个方面。我们发现单次注射可卡因不会改变 LTP。然而，用尼古丁预处理，然后再注射一次可卡因会导致 LTP 显著增强。尼古丁的这种启动效应是单向的：如果可卡因在尼古丁之前给予，则不会增强 LTP。尼古丁和可卡因引起的易化作用可被多巴胺 D1/D5 受体拮抗剂（SKF 83566）的口服给药阻断，并且可被 D1/D5 激动剂（SKF 38393）增强。组蛋白去乙酰化抑制剂 suberoylanilide hydroxamic acid（SAHA）的应用模拟了尼古丁对可卡因的启动作用。相比之下，在 CREB 结合蛋白（CBP）单倍不足的基因修饰小鼠中，尼古丁对可卡因的启动作用被阻断，并且仅具有一个功能性 CBP 等位基因，因此组蛋白乙酰化减少。这些结果表明，海马的 DG 是导致尼古丁对可卡因的启动作用的重要脑区。此外，多巴胺 D1 受体/PKA 信号通路的激活和组蛋白去乙酰化/CBP 介导的转录都需要 DG 中的尼古丁启动效应。
