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首页> 外文期刊>Addiction biology >Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner
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Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner

机译：Amygdala AMPA受体活动的增强选择性地以Camkii依赖的方式促进升级的酒精自我管理

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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 alpha-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 minutes) 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 with 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-reinforced but not sucrose-reinforced responding and was ineffective following intra-AcbC infusion. Because 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 myristolated autocamtide-2-related inhibitory peptide (m-AIP) dose-dependently reduced alcohol self-administration. A subthreshold 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.
机译：日益增长的证据表明，通过篡夺与奖励相关的脑区中的神经塑性的谷氨酸连接机制，滥用滥用药物对个体的控制。因此，我们已经表明，氨基达达拉中的谷氨酸α-氨基-3-羟基-5-甲基-4-异恶唑基酸受体（AMPAR）活性是醇的阳性增强作用所必需的，这是初始阶段的成瘾阶段。然而，如果Amygdala的增强AMPAR活动有利于酒精自我管理，这是未知的，这是谷氨酸谷氨酸假设的籽粒前提。在这里，我们表明，低剂量醇（0.6g / kg / 30分钟）自我给药增加了中央杏仁菌（CEA），基石孢子醛和核心核心（与行为匹配（非药物）蔗糖对照相比，选择性地培养醇优选的P-大鼠ACBC。通过在酒精自我施用之前通过CEA和ACBC中的特异性阳性调节剂，ANIRACETAM的特异性输注来评估增强的AMPAR活性的功能作用。 CEA aniracetam内部增加醇增强但不蔗糖增强的响应，并且在ACBC内输注后无效。因为Glua1 S831是Ca2 + /钙调蛋白依赖性蛋白激酶II（Camkii）底物，所以我们寻求确定增强酒精自我管理的AMPAR调节是否依赖于Camkii活动。 CEA内输注细胞可渗透的CAMKII肽抑制剂MyRistolated AutoChide-2相关抑制肽（M-AIP）剂量依赖性降低醇自我给药。 M-AIP的亚阈值剂量也阻断了Aniracetam诱导的酒精自我给药升级，证明了醇增强的氨分析介导的饮用性需要在Amygdala中的Camkii活性。增强的棉花末期可塑性连续的AMPAR-CAMKII信号的活性可以通过增加的成瘾阶段增加的阳性增强来促进升级的酒精使用。

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