Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands.
Addict Biol. 2017 Nov;22(6):1883-1894. doi: 10.1111/adb.12547. Epub 2017 Sep 22.
Drug addiction is associated with aberrant memory and permanent functional changes in neural circuits. It is known that exposure to drugs like morphine is associated with positive emotional states and reward-related memory. However, the underlying mechanisms in terms of neural plasticity in the ventral hippocampus, a region involved in associative memory and emotional behaviors, are not fully understood. Therefore, we measured adult neurogenesis, dendritic spine density and brain-derived neurotrophic factor (BDNF) and TrkB mRNA expression as parameters for synaptic plasticity in the ventral hippocampus. Male Sprague Dawley rats were subjected to the CPP (conditioned place preference) paradigm and received 10 mg/kg morphine. Half of the rats were used to evaluate neurogenesis by immunohistochemical markers Ki67 and doublecortin (DCX). The other half was used for Golgi staining to measure spine density and real-time quantitative reverse transcription-polymerase chain reaction to assess BDNF/TrkB expression levels. We found that morphine-treated rats exhibited more place conditioning as compared with saline-treated rats and animals that were exposed to the CPP without any injections. Locomotor activity did not change significantly. Morphine-induced CPP significantly increased the number of Ki67 and DCX-labeled cells in the ventral dentate gyrus. Additionally, we found increased dendritic spine density in both CA1 and dentate gyrus and an enhancement of BDNF/TrkB mRNA levels in the whole ventral hippocampus. Ki67, DCX and spine density were significantly correlated with CPP scores. In conclusion, we show that morphine-induced reward-related memory is associated with neural and synaptic plasticity changes in the ventral hippocampus. Such neural changes could underlie context-induced drug relapse.
药物成瘾与神经回路的异常记忆和永久性功能改变有关。已知，像吗啡这样的药物暴露与积极的情绪状态和与奖励相关的记忆有关。然而，涉及联想记忆和情绪行为的腹侧海马体中的神经可塑性的潜在机制尚未完全了解。因此，我们测量了成年神经发生、树突棘密度和脑源性神经营养因子（BDNF）和 TrkB mRNA 表达作为腹侧海马体突触可塑性的参数。雄性 Sprague Dawley 大鼠接受 CPP（条件性位置偏好）范式，并接受 10mg/kg 吗啡。一半的大鼠用于通过免疫组织化学标志物 Ki67 和双皮质素（DCX）评估神经发生。另一半用于高尔基染色测量棘密度，并进行实时定量逆转录聚合酶链反应评估 BDNF/TrkB 表达水平。我们发现，与盐水处理的大鼠和未接受任何注射的 CPP 暴露的动物相比，吗啡处理的大鼠表现出更多的位置条件。运动活性没有显著变化。吗啡诱导的 CPP 显著增加了腹侧齿状回中 Ki67 和 DCX 标记细胞的数量。此外，我们发现 CA1 和齿状回中的树突棘密度增加，整个腹侧海马体中的 BDNF/TrkB mRNA 水平增强。Ki67、DCX 和棘密度与 CPP 评分显著相关。总之，我们表明，吗啡诱导的与奖励相关的记忆与腹侧海马体中的神经和突触可塑性变化有关。这种神经变化可能是导致情境诱导药物复发的基础。
