被盖腹侧区
伏隔核
氧化应激
多巴胺
化学
内分泌学
多巴胺能
内科学
有条件地点偏好
下调和上调
上瘾
药理学
医学
神经科学
生物
生物化学
基因
作者
Minmin Sun,Chao Wu,Lixin Liu,Gu Li,Zihao Wang,Feng Xing,Donglin Zhu
标识
DOI:10.1016/j.bcp.2023.115578
摘要
The brain renin–angiotensin system (RAS) has recently been implicated in the development of substance abuse and addiction. However, the integrative roles of the two counter-regulating RAS arms, including the ACE1/Ang II/AT1R axis and the ACE2/Ang(1–7)/MasR axis, in alcohol addiction remain unclear. Using the 20% ethanol intermittent-access two-bottle-choice (IA2BC) paradigm, we observed significant alcohol preference and addictive behaviors in rats. Additionally, we observed significant disruption in the RAS and redox homeostasis in the ventral tegmental area (VTA), as indicated by upregulation of ACE1 activities, Ang II levels, AT1R expression, and glutathione disulfide contents, as well as downregulation of ACE2 activities, Ang(1–7) levels, MasR expression and glutathione content. Moreover, dopamine accumulated in the VTA and nucleus accumbens of IA2BC rats. Intra-VTA infusion of the antioxidant tempol substantially attenuated RAS imbalance and addictive behaviors. Intra-VTA infusion of the ACE1 inhibitor captopril significantly reduced oxidative stress, alcohol preference, addictive behaviors, and dopamine accumulation, whereas intra-VTA infusion of the ACE2 inhibitor MLN4760 had the opposite effects. The anti-addictive effects of the ACE2/Ang(1–7)/MasR axis were further observed using intra-VTA infusion of Ang(1–7) and a MasR-specific antagonist A779. Therefore, our findings suggest that excessive alcohol intake causes RAS imbalance via oxidative stress, and that a dysregulated RAS in the VTA contributes to alcohol addiction by stimulating oxidative stress and dopaminergic neurotransmission. Breaking the vicious cycle of RAS imbalance and oxidative stress using brain-permeable antioxidants, ACE1 inhibitors, ACE2 activators, or Ang(1–7) mimetics thus represents a promising strategy for combating alcohol addiction.
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