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Acetaldehyde Excitation of Lateral Habenular Neurons via Multiple Cellular Mechanisms
Journal of Neuroscience ( IF 5.3 ) Pub Date : 2021-09-08 , DOI: 10.1523/jneurosci.2913-20.2021
Weiyuan Huang , Wanhong Zuo , Lixin Chen , Liwei Wang , George Tewfik , Rao Fu , Jiayi Zheng , Ding Li , Jiang-Hong Ye

Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal mechanisms underlying ACD's aversive effect, however, are poorly understood. The lateral habenula (LHb), a regulator of midbrain monoaminergic centers, is activated by negative valence events. Although the LHb has been linked to the aversive responses of several abused drugs, including ethanol, little is known about ACD. We, therefore, assessed ACD's action on LHb neurons in rats. The results showed that intraperitoneal injection of ACD increased cFos protein expression within the LHb and that intra-LHb infusion of ACD induced conditioned place aversion in male rats. Furthermore, electrophysiological recording in brain slices of male and female rats showed that bath application of ACD facilitated spontaneous firing and glutamatergic transmission. This effect of ACD was potentiated by an aldehyde dehydrogenase (ALDH) inhibitor, disulfiram (DS), but attenuated by the antagonists of dopamine (DA) receptor (DAR) subtype 1 (SCH23390) and subtype 2 (raclopride), and partly abolished by the pretreatment of DA or DA reuptake blocker (GBR12935; GBR). Moreover, application of ACD initiated a depolarizing inward current (IACD) and enhanced the hyperpolarizing-activated currents in LHb neurons. Bath application of Rp-cAMPs, a selective cAMP-PKA inhibitor, attenuated ACD-induced potentiation of EPSCs and IACD. Finally, bath application of ZD7288, a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channels, attenuated ACD-induced potentiation of firing, EPSCs, and IACD. These results show that ACD exerts its aversive property by exciting LHb neurons via multiple cellular mechanisms, and new treatments targeting the LHb may be beneficial for alcoholism.

SIGNIFICANCE STATEMENT Acetaldehyde (ACD) has been considered aversive peripherally and rewarding centrally. However, whether ACD has a central aversive property is unclear. Here, we report that ACD excites the lateral habenula (LHb), a brain region associated with aversion and negative valence, through multiple cellular and molecular mechanisms. Intra-LHb ACD produces significant conditioned place aversion. These results suggest that ACD's actions on the LHb neurons might contribute to its central aversive property and new treatments targeting the LHb may be beneficial for alcoholism.



中文翻译:

通过多种细胞机制对外侧缰神经元进行乙醛激发

乙醛 (ACD) 是乙醇的第一种代谢产物,与乙醇的多种作用有关,包括增强作用和厌恶作用。然而,人们对 ACD 厌恶效应背后的神经元机制知之甚少。外侧缰核 (LHb) 是中脑单胺能中心的调节器,由负价事件激活。尽管 LHb 与几种滥用药物(包括乙醇)的厌恶反应有关,但对 ACD 知之甚少。因此,我们评估了 ACD 对大鼠 LHb 神经元的作用。结果表明,腹膜内注射 ACD 增加了 LHb 内 cFos 蛋白的表达,而 LHb 内输注 ACD 会诱导雄性大鼠的条件性位置厌恶。此外,雄性和雌性大鼠脑切片的电生理记录表明,ACD 的沐浴应用促进了自发性放电和谷氨酸能传递。ACD 的这种作用被醛脱氢酶 (ALDH) 抑制剂双硫仑 (DS) 增强,但被多巴胺 (DA) 受体 (DAR) 亚型 1 (SCH23390) 和亚型 2 (raclopride) 的拮抗剂减弱,并被部分消除DA或DA再摄取阻滞剂(GBR12935;GBR)的预处理。此外,ACD 的应用引发了去极化的内向电流(并通过 DA 或 DA 再摄取阻滞剂(GBR12935;GBR)的预处理部分消除。此外,ACD 的应用引发了去极化的内向电流(并通过 DA 或 DA 再摄取阻滞剂(GBR12935;GBR)的预处理部分消除。此外,ACD 的应用引发了去极化的内向电流(I ACD ) 并增强 LHb 神经元中的超极化激活电流。Rp-cAMPs(一种选择性 cAMP-PKA 抑制剂)的浴应用减弱了 ACD 诱导的 EPSCs 和I ACD的增强作用。最后,ZD7288(超极化激活的环核苷酸门控通道的选择性阻断剂)的浴应用减弱了 ACD 诱导的放电、EPSC 和I ACD增强。这些结果表明,ACD 通过多种细胞机制激发 LHb 神经元发挥其厌恶特性,针对 LHb 的新疗法可能有益于酗酒。

重要性声明乙醛 (ACD) 被认为是外周厌恶和中枢奖励。然而,ACD 是否具有中枢厌恶属性尚不清楚。在这里,我们报告说 ACD 通过多种细胞和分子机制激发外侧缰核 (LHb),这是一个与厌恶和负价相关的大脑区域。LHb 内 ACD 产生显着的条件性位置厌恶。这些结果表明 ACD 对 LHb 神经元的作用可能有助于其中枢厌恶特性,针对 LHb 的新疗法可能对酗酒有益。

更新日期:2021-09-09
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