健康与遗传心理学研究室知识库

Opioid dependence is a chronic relapsing disorder in the brain characterized by compulsive drug taking and the emergence of withdrawal syndrome after cessation of drug taking. Negative affection induced by drugs-withdraw is one of powerful reinforcers, which contributes so much to the relapse or sustained drug abuse. According to reports the morphine-indeuced withdrawal was correlated with the activation of the dorsal hippocampus (DH). The elevated level of Ca2+ in DH is not only a sign of its activation, but also is the central link among the intracellular signal transduction. Therefore, the regulation of calcium channel on Ca2+ transmembrane transport is the key factors of negative emotion memory induced by morphine withdrawal. L-type voltage gated calcium channels (LTCCs) can regulate the activity of some other types of calcium channels such as NMDA and RyR receptors, changes the intracellular Ca2+, thereby regulating morphine withdrawal. The present proposal based on this hypothesis, using conditioned place aversion (CPA) paradigm in rats, we will investigate whether the level of intracellular Ca2+ in hippampal CA1 was increased after the injection of naloxone in chronic morphine-dependent rats. In addition, the different effects of LTCCs subtypes Cav1.2 and Cav1.3 on the CPA induced by morphine withdrawal will also be examined. Moreover, we will test what were the downstream signal pathways of LTCCs during the acquisition of negative emotion memory induced by morphine withdrawal. The main results are as follows:

1 .The level of intracellular Ca2+ in hippampal CA1 was increased after the injection of naloxone in chronic morphine-dependent rats. And this increase was dependent on the activity of LTCCs.

2. Intra-CA1 administration of LTCCs antagionst blocked the acquisition of CPA induced by morphine withdrawal, indicating that LTCCs was involved in the acquisition of negative emotin memory in the CA1 of rats.

3. After the injection of naloxone in chronic morphine-dependent rats, the expression of Cav1.3 was obviously increased in the CAl，whereas Cavl.2 protein expresson was significantly increased in the CA1 after the acquisition of morphine CPA. These results suggested that Cavl.3 specifically regulate morphine withdrawal, Cavl.2 selectively involved in the acquisition of negative emotion memory in the CA1.

4. Cavl.2 regulated the acquisition of morphine CPA via activating the MAPK-ERIC signaling pathway in the CA1.

药物成瘾是一种慢性复发性脑病，以强迫用药和停药后出现戒断症状为主要特征。吗啡戒断所致的仄恶负性记忆是最强的负性强化因子之一，导致复吸和持续的药物使用。据报道，吗啡戒断症状的产生与背侧海马(dorsal Hippocampus,DH)脑区的激活直接相关。DH胞内游离Ca2+的增加不仅是其活化的标志，也是胞内信号转导的中心环节。因此，钙通道对Cat十跨膜转运的调控是戒断所致负性记忆形成的关键因素。L型电压门控钙通道(L-type voltage dependent calciumchannels, LTCCs)能够调节其他类型钙通道如IVMDA和RyR的活性，改变胞内Ca2+水平，从而调控吗啡戒断负性记忆。本研究从这一假设出发，以大鼠条件位置厌恶(conditioned place aversion, CPA)为模型，首先，利用荧光内窥成像技术检钡(吗啡戒断过程中海马CA1区是否被激活，并进一步确定其激活是否依赖于LTCCs。其次，利用行为药理学技术检测LTCCs是否介导CPA的获得，并比较研究LTCCs不同亚型Cavl.2和Cav1.3在CPA获得中作用的异同。在此基础上，利用分子生物学等技术探索LTCCs调控CPA获得过程的分子机制。本研究的主要结论如下:

1) LTCCs调控吗啡戒断诱导的海马CA1脑区的激活。

2)海马CA1区LTCCs介导吗啡戒断所致负性情绪记忆(CPA)的获得过程。

3)海马CA1区Cavl.3选择性地调控吗啡戒断，而Cavl.2特异性地介导戒断所致负性情绪记忆(CPA)的获得。

4)海马CA1区Cav 1.2通过调节下游MAPK-ERK信号通路从而调控戒断所致负性情绪记忆(CPA)的获得过程。