Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens
Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens
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DOI：
10.1111/bph.12690
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发表时间：
2014-07-01
影响因子：
7.3
通讯作者：
Bartlett, S. E.
中科院分区：
文献类型：
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作者：
Feduccia, A. A.;Simms, J. A.;Bartlett, S. E.
伐尼克兰是一种神经元烟碱乙酰胆碱受体（nAChR）调节剂，可减少啮齿动物和人类的乙醇消耗。提出的伐尼克兰减少乙醇消耗的作用机制是通过腹侧被盖区（VTA）中含α 4* 的nAChR调节丘脑核（NAc）中的多巴胺（DA）释放。然而，突触前nAChR的多巴胺能终端在NAC已被证明直接调制多巴胺能信号独立的神经元活动的腹侧被盖区。在这项研究中，我们确定是否nAChRs在NAC发挥作用，在伐尼克兰的影响，对乙醇consumption.Experimental APPROACHRATS进行了培训，消耗乙醇使用的admittent-access两瓶选择协议为10周。将伐尼克兰或溶媒微量注入NAc（核、壳或核-壳边界）或VTA（前或后）后，测量乙醇摄入量。使用体内微透析和体外快速扫描循环伏安法（FSCV）测量伐尼克兰治疗对NAc中DA释放的影响。关键词将伐尼克兰微输注到NAc核心和核-壳边界，但不输注到NAc壳或VTA，减少长期乙醇消耗后的乙醇摄入。在微透析过程中，一个显着的增强，在nabbal DA释放发生后，系统性管理的伐尼克兰和FSCV表明，伐尼克兰也改变了诱发释放DA在NAc. CONCLITIONS和IMPLICATIONsAfter长期乙醇消耗，伐尼克兰在NAc减少乙醇摄入量，这表明突触前nAChRs在NAc是重要的介导伐尼克兰对乙醇消耗的影响。
BACKGROUND AND PURPOSEVarenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via alpha 4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption.EXPERIMENTAL APPROACHRats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV).KEY RESULTSMicroinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc.CONCLUSION AND IMPLICATIONSFollowing long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption.