Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner.
Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner.
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DOI：
10.1111/adb.12357
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发表时间：
2017-05
影响因子：
3.4
通讯作者：
Hodge CW
中科院分区：
文献类型：
--
作者：
Cannady R;Fisher KR;Graham C;Crayle J;Besheer J;Hodge CW
越来越多的证据表明，滥用药物通过篡夺与谷氨酸相关的神经可塑性机制在奖励相关的大脑区域获得对个体的控制。因此，我们已经证明，杏仁核中的谷氨酸α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）活性是酒精的积极强化作用所必需的，这是成瘾初始阶段的基础。然而，尚不清楚杏仁核中AMPAR活性的增强是否有助于酒精自我给药，这是谷氨酸成瘾假说的核心前提。本研究表明，与行为匹配（非药物）蔗糖对照相比，低剂量酒精（0.6 g/kg/30分钟）自我给药增加了选择性繁殖的偏好酒精的p大鼠中央杏仁核（CeA）、杏仁核基底外侧和伏隔核（AcbC）中AMPAR亚型GluA1 S831 （pGluA1 S831）的磷酸化（激活）。在自我给药前，通过在CeA和AcbC中特定部位注射AMPAR阳性调节剂阿尼西坦来评估增强AMPAR活性的功能作用。cea内的阿尼西坦增加了酒精增强的反应，但没有增加糖增强的反应，并且在acbc内输注后无效。由于GluA1 S831是Ca2+/钙调素依赖性蛋白激酶II （CaMKII）底物，我们试图确定AMPAR对增强酒精自我给药的调节是否依赖于CaMKII活性。cea内输注细胞渗透性CaMKII肽抑制剂m-AIP剂量依赖性地减少酒精自我给药。低于阈值剂量的m-AIP也阻断了阿尼西坦诱导的酒精自我给药的增加，这表明ampar介导的酒精增强需要杏仁核中CaMKII的活性。杏仁核中与可塑性相关的AMPAR-CaMKII信号活动的增强，可能会在成瘾的初始阶段通过增加正强化来促进酒精使用的升级。
Growing evidence indicates that drugs of abuse gain control over the individual by usurping glutamate-linked mechanisms of neuroplasticity in reward-related brain regions. Accordingly, we have shown that glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activity in the amygdala is required for the positive reinforcing effects of alcohol, which underlie the initial stages of addiction. It is unknown, however, if enhanced AMPAR activity in the amygdala facilitates alcohol self-administration, which is a kernel premise of glutamate hypotheses of addiction. Here we show that low-dose alcohol (0.6 g/kg/30-min) self-administration increases phosphorylation (activation) of AMPAR subtype GluA1 S831 (pGluA1 S831) in the central amygdala (CeA), basolateral amygdala, and nucleus accumbens core (AcbC) of selectively bred alcohol-preferring P-rats as compared to behavior-matched (non-drug) sucrose controls. The functional role of enhanced AMPAR activity was assessed via site-specific infusion of the AMPAR positive modulator, aniracetam, in the CeA and AcbC prior to alcohol self-administration. Intra-CeA aniracetam increased alcohol- but not sucrose-reinforced responding, and was ineffective following intra-AcbC infusion. Since GluA1 S831 is a Ca2+/calmodulin-dependent protein kinase II (CaMKII) substrate, we sought to determine if AMPAR regulation of enhanced alcohol self-administration is dependent on CaMKII activity. Intra-CeA infusion of the cell-permeable CaMKII peptide inhibitor m-AIP dose-dependently reduced alcohol self-administration. A sub-threshold dose of m-AIP also blocked the aniracetam-induced escalation of alcohol self-administration, demonstrating that AMPAR-mediated potentiation of alcohol reinforcement requires CaMKII activity in the amygdala. Enhanced activity of plasticity-linked AMPAR-CaMKII signaling in the amygdala may promote escalated alcohol use via increased positive reinforcement during the initial stages of addiction.