Involvement of AMPA/Kainate Glutamate Receptor in the Extinction and Reinstatement of Morphine-Induced Conditioned Place Preference: A Behavioral and Molecular Study
Involvement of AMPA/Kainate Glutamate Receptor in the Extinction and Reinstatement of Morphine-Induced Conditioned Place Preference: A Behavioral and Molecular Study
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DOI：
10.1007/s10571-016-0371-2
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发表时间：
2016-04
影响因子：
4
通讯作者：
A. Siahposht-Khachaki;Z. Fatahi;A. Yans;F. Khodagholi;A. Haghparast
中科院分区：
文献类型：
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作者：
A. Siahposht-Khachaki;Z. Fatahi;A. Yans;F. Khodagholi;A. Haghparast
伏隔核、腹侧被盖区、前额叶皮质(PFC)和海马区(HIP)等中脑边缘区域的谷氨酸受体是药物奖赏机制的组成部分，可调节奖赏系统中多巴胺能神经元的放电模式。此外，多项研究表明，cAMP反应元件结合蛋白(CREB)和c-fos在吗啡诱导的条件性位置偏爱(CPP)中起重要作用。因此，在本研究中，我们观察了侧脑室注射不同剂量的CNQX或赋形剂，在消退期或恢复吗啡诱导的CPP期间，伏核(NAC)、HIP和PFC内磷酸化CREB(p-CREB)和c-fos诱导的变化。所有组均完成CPP程序；随后，使用ethovision软件记录条件反射评分。行为测试记录后，解剖NAC区、HIP区和PFC区，用Western印迹法检测p-CREB/CREB比值和c-fos水平。结果表明，CNQX可显著缩短吗啡CPP的消退时间。此外，灭绝期后侧脑室微量注射CNQX可降低吗啡CPP的恢复。在分子切片上，脑室注射不同剂量的CNQX后，治疗组上述各指标均呈剂量依赖性降低，但消退前注射组无明显变化。提示AMPA受体拮抗剂可降低PFC、NAC和HIP的p-CREB/CREB比值和c-fos水平。药物记忆再巩固的调节可能有助于加快药物奖赏的消退和药物寻觅行为的减弱。
Glutamate receptors in mesolimbic areas such as the nucleus accumbens, ventral tegmental area, prefrontal cortex (PFC), and hippocampus (HIP) are a component of the mechanisms of drug-induced reward and can modulate the firing pattern of dopaminergic neurons in the reward system. In addition, several lines of study have indicated that cAMP response element-binding protein (CREB) and c-fos have important role in morphine-induced conditioned place preference (CPP) induced by drugs of abuse, such as morphine, cocaine, nicotine, and alcohol. Therefore, in the present study, we investigated the changes in phosphorylated CREB (p-CREB) and c-fos induction within the nucleus accumbens (NAc), HIP, and PFC after intracerebroventricular (ICV) administration of different doses of CNQX or vehicle during extinction period or reinstatement of morphine-induced CPP. In all groups, the CPP procedure was done; afterward, the conditioning scores were recorded by Ethovision software. After behavioral test recording, we dissected out the NAc, HIP, and PFC regions and measured the p-CREB/CREB ratio and c-fos level by Western blot analysis. Our results showed that administration of CNQX significantly shortened the extinction of morphine CPP. Besides, ICV microinjection of CNQX following extinction period decreased the reinstatement of morphine CPP in extinguished rats. In molecular section, in treatment group, all mentioned factors were dose-dependently decreased in comparison with vehicle group (DMSO) after ICV microinjection of different doses of CNQX but not in pre-extinction microinjection. These findings suggested that antagonism of AMPA receptor decreased p-CREB/CREB ratio and c-fos level in the PFC, NAc, and HIP. Modulation of the drug memory reconsolidation may be useful for faster extinction of drug-induced reward and attenuation of drug-seeking behavior.