Department of Psychiatry, Duke University Medical Center, and Research Service, Veterans Administration Medical Center, Durham, North Carolina 27705, USA.
J Pharmacol Exp Ther. 2013 Jul;346(1):130-7. doi: 10.1124/jpet.112.202903. Epub 2013 Apr 15.
Human and animal studies indicate that κ-opioid receptors (KORs) are involved in ethanol drinking and dependence (Xuei et al., 2006; Walker and Koob, 2008; Walker et al., 2011). Using in vitro single-cell recording techniques in mouse brain slices, we examined the physiologic effects of KOR activation in the central amygdala (CeA) on GABAergic neurotransmission and its interaction with acute ethanol. A selective KOR agonist (U69593, 1 μM) diminished evoked GABAergic inhibitory postsynaptic currents (IPSCs) by 18% (n = 10), whereas blockade of KORs with a selective antagonist (nor-binaltorphimine, 1 μM) augmented the baseline evoked GABAergic IPSCs by 14% (P < 0.01; n = 34), suggesting that the KOR system contributes to tonic inhibition of GABAergic neurotransmission in the CeA. In addition, the enhancement by acute ethanol of GABAergic IPSC amplitudes was further augmented by pharmacologic blockade of KORs, from 14% (n = 36) to 27% (n = 26; P < 0.01), or by genetic deletion of KORs, from 14% in wild-type mice (n = 19) to 34% in KOR knockout mice (n = 13; P < 0.01). Subsequent experiments using tetrodotoxin to block activity-dependent neurotransmission suggest that KORs regulate GABA release at presynaptic sites. Our data support the idea that KORs modulate GABAergic synaptic responses and ethanol effects as one of multiple opioid system-dependent actions of ethanol in the CeA, possibly in a circuit-specific manner.
人体和动物研究表明，κ-阿片受体（KORs）参与了乙醇的摄入和依赖（Xuei 等人，2006 年；Walker 和 Koob，2008 年；Walker 等人，2011 年）。我们在小鼠脑切片中使用体外单细胞记录技术，研究了中央杏仁核（CeA）中 KOR 激活对 GABA 能神经传递的生理影响及其与急性乙醇的相互作用。一种选择性的 KOR 激动剂（U69593，1 μM）使诱发的 GABA 能抑制性突触后电流（IPSCs）减少了 18%（n = 10），而用选择性拮抗剂（nor-binaltorphimine，1 μM）阻断 KOR 则使基线诱发的 GABA 能 IPSCs 增加了 14%（P < 0.01；n = 34），这表明 KOR 系统有助于 CeA 中 GABA 能神经传递的紧张性抑制。此外，急性乙醇对 GABA 能 IPSC 幅度的增强作用，通过 KOR 的药理学阻断进一步增强，从 14%（n = 36）增强到 27%（n = 26；P < 0.01），或通过 KOR 的基因缺失增强，从野生型小鼠的 14%（n = 19）增强到 KOR 敲除小鼠的 34%（n = 13；P < 0.01）。随后使用河豚毒素阻断活动依赖性神经传递的实验表明，KOR 调节 GABA 释放于突触前部位。我们的数据支持这样一种观点，即 KOR 调节 GABA 能突触反应和乙醇的作用，这是乙醇在 CeA 中多种阿片系统依赖性作用之一，可能是以特定回路的方式。
