Huang Chien-Hsuan, Yu Yang-Jung, Chang Chih-Hua, Gean Po-Wu
Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan.
J Neurochem. 2016 Apr;137(2):216-25. doi: 10.1111/jnc.13525. Epub 2016 Jan 24.
Addiction is thought to be a memory process between perception and environmental cues and addicted patients often relapse when they come into contact with the drug-related context once again. Here, we used a conditioned place preference protocol to seek a more effective extinction methodology of methamphetamine (METH) memory and delineate its underlying mechanism. Conditioning METH for 3 days in mice markedly increased the time spent in the METH-paired compartment. Then the mice were conditioned with saline for 6 days, from day 6 to day 11, a procedure termed extinction training. However, METH memory returned after a priming injection of METH. We prolonged extinction duration from 6 to 10 days and found that this extensive extinction (EE) training prevented priming effect. At the molecular level, we discovered that prolonged extinction training reversed the METH-conditioned place preference-induced increase in surface expression of GluA2 and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/NMDA ratio in the basolateral amygdala. In addition, we found that extinction with metabotropic glutamate receptor 5 (mGluR5) activation had similar results to EE: reduced relapse after extinction, decreased synaptic AMPA receptors AMPARs and the AMPA/NMDA ratio. On the contrary, EE with mGluR5 inhibition suppressed the results of EE. These data indicate that EE training-elicited inhibition of METH-primed reinstatement is mediated by the mGluR5. Conditioning mice with methamphetamine place preference (METH CPP) increases surface expression of AMPA receptors (AMPARs) in the basolateral amygdala. We found prolongation of extinction duration from 6 to 10 days prevented priming effect. At the molecular level, we discovered that extensive extinction (EE) reversed the METH CPP-induced increase in surface expression of GluA2 and AMPA/NMDA ratio. In addition, we found that extinction with the metabotropic glutamate receptor 5 (mGluR5) activation had similar results to EE: reduced relapse after extinction, decreased synaptic AMPARs and the AMPA/NMDA ratio. On the contrary, EE with mGluR5 inhibition suppressed the results of EE. These data indicate that EE training-elicited inhibition of METH-primed reinstatement is mediated by mGluR5 (PAM: positive allosteric modulator).
成瘾被认为是一种介于感知和环境线索之间的记忆过程，成瘾患者在再次接触与药物相关的环境时往往会复发。在此，我们使用条件性位置偏好实验来寻找一种更有效的消除甲基苯丙胺（METH）记忆的方法，并阐明其潜在机制。在小鼠中对METH进行3天的条件化处理显著增加了在与METH配对的隔室中停留的时间。然后在第6天至第11天，用生理盐水对小鼠进行6天的条件化处理，此过程称为消退训练。然而，在一次METH引发注射后，METH记忆又恢复了。我们将消退持续时间从6天延长至10天，发现这种延长的消退（EE）训练可防止引发效应。在分子水平上，我们发现延长的消退训练逆转了METH条件性位置偏好诱导的基底外侧杏仁核中GluA2表面表达增加以及α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）/N-甲基-D-天冬氨酸（NMDA）比值升高。此外，我们发现用代谢型谷氨酸受体5（mGluR5）激活进行消退训练与EE有相似的结果：消退后复发减少、突触AMPA受体（AMPARs）减少以及AMPA/NMDA比值降低。相反，用mGluR5抑制进行EE训练则抑制了EE的效果。这些数据表明，EE训练引发的对METH引发复吸的抑制是由mGluR5介导的。用甲基苯丙胺位置偏好（METH CPP）对小鼠进行条件化处理可增加基底外侧杏仁核中AMPA受体（AMPARs）的表面表达。我们发现将消退持续时间从6天延长至10天可防止引发效应。在分子水平上，我们发现延长的消退（EE）逆转了METH CPP诱导的GluA2表面表达增加以及AMPA/NMDA比值升高。此外，我们发现用代谢型谷氨酸受体5（mGluR5）激活进行消退训练与EE有相似的结果：消退后复发减少、突触AMPARs减少以及AMPA/NMDA比值降低。相反，用mGluR5抑制进行EE训练则抑制了EE的效果。这些数据表明，EE训练引发的对METH引发复吸的抑制是由mGluR5介导的（PAM：正变构调节剂）。
