Fu Rao, Mei Qinghua, Zuo Wanhong, Li Jing, Gregor Danielle, Bekker Alex, Ye Jianghong
Department of Anesthesiology, Pharmacology, Physiology & Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical SchoolNewark, New Jersey 07103, USA.
Department of Pharmacy, Guangdong Second Provincial General HospitalGuangzhou 510317, China.
Int J Physiol Pathophysiol Pharmacol. 2017 Dec 25;9(6):217-230. eCollection 2017.
It is unclear how social drinking can contribute to the development of addiction in susceptible individuals. However, alcohol's aversive properties are a well-known factor contributing to its abuse. The lateral habenula (LHb) is a key brain structure responding to various aversive stimuli, including those related to alcohol. We recently reported that ethanol at 10 mM or less that can be achieved by social drinking activates many LHb neurons and drives aversive conditioning. The current study sought to identify LHb circuits that are activated by a low-dose of ethanol using immunohistochemistry and anatomic tracing techniques on adult Sprague-Dawley rats. We showed here that an intraperitoneal injection of ethanol (0.25 g/kg), resulting in a blood ethanol concentration of 5.6 mM, significantly increased the number of cFos immunoreactive (IR) neurons in the LHb. Most of the ethanol-activated cFos-IR LHb neurons expressed vGluT2 (vesicular glutamate transporters 2, a marker of a glutamatergic phenotype). These LHb neurons projected to the ventral tegmental area (VTA), rostromedial tegmental nucleus (RMTg), and dorsal raphe. Moreover, injections of the anterograde tracer AAV-CaMKIIa-eGFP into the lateral hypothalamus produced a significant amount of labeled fibers with vGluT2 positive terminals on the ethanol-activated LHb cells. These results indicate that the LHb neurons stimulated by a low-dose of ethanol project to the VTA, RMTg, and dorsal raphe, and receive excitatory projections from the lateral hypothalamus. These neurocircuits may play a crucial role in mediating the initial aversive effects produced by a low-dose of ethanol.
尚不清楚社交性饮酒如何导致易感个体成瘾。然而，酒精的厌恶特性是导致其被滥用的一个众所周知的因素。外侧缰核（LHb）是对各种厌恶刺激做出反应的关键脑结构，包括与酒精相关的刺激。我们最近报道，社交性饮酒所能达到的10 mM及以下的乙醇会激活许多LHb神经元并驱动厌恶条件反射。本研究旨在利用免疫组织化学和解剖追踪技术，在成年Sprague-Dawley大鼠中识别被低剂量乙醇激活的LHb神经回路。我们在此表明，腹腔注射乙醇（0.25 g/kg），导致血液乙醇浓度为5.6 mM，显著增加了LHb中cFos免疫反应性（IR）神经元的数量。大多数被乙醇激活的cFos-IR LHb神经元表达vGluT2（囊泡谷氨酸转运体2，一种谷氨酸能表型的标志物）。这些LHb神经元投射到腹侧被盖区（VTA）、嘴内侧被盖核（RMTg）和中缝背核。此外，将顺行示踪剂AAV-CaMKIIa-eGFP注射到外侧下丘脑，在被乙醇激活的LHb细胞上产生了大量带有vGluT2阳性终末的标记纤维。这些结果表明，低剂量乙醇刺激的LHb神经元投射到VTA、RMTg和中缝背核，并接受来自外侧下丘脑的兴奋性投射。这些神经回路可能在介导低剂量乙醇产生的初始厌恶效应中起关键作用。
