Chan Amy E, Driscoll Gillian S, Usmani Zaynah, Ozburn Angela R
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland Alcohol Research Center, Portland, OR, 97239, USA.
Veterans Affairs Portland Health Care System, Research and Development Service, Portland, OR, 97239, USA.
Biol Sex Differ. 2025 Aug 28;16(1):66. doi: 10.1186/s13293-025-00745-0.
Women tend to progress from initial alcohol use to dependence more rapidly than men, a phenomenon known as the "telescoping effect". This suggests different consequences of early alcohol use, which can impact the development of an Alcohol Use Disorder (AUD). Previous evidence demonstrated that nucleus accumbens core (NAcC) chemogenetic manipulations resulted in opposite effects on binge-like drinking [stimulation decreased ethanol intake in C57BL/6J (B6) females, while inhibition decreased intake in males]. In humans, ethanol cue conditioning is linked to the positive subjective effects of alcohol intake and intoxication. We tested the hypothesis that chemogenetic manipulation of NAcC activity alters ethanol reward (measured by conditioned place preference, CPP) in a sex-specific manner.
In Experiment 1, surgery naïve B6 mice (n = 11-12/sex/treatment) underwent an ethanol CPP protocol and were administered the Designer Receptors Exclusively Activated by Designer Drugs (DREADD) actuator clozapine-N-oxide (CNO, 1 mg/kg) or vehicle prior to ethanol (2 g/kg) conditioning. In Experiment 2, B6 mice underwent surgery to deliver control (mCherry), excitatory (hM3Dq), or inhibitory (hM4Di) DREADDs to the NAcC (n = 8-13/sex/treatment). After recovery, mice underwent ethanol CPP as in Experiment 1. CPP was conducted in a 3-chamber apparatus. Time spent in each chamber was recorded during the pre-test (before conditioning), and the test (after 4 ethanol and 4 saline conditioning sessions). Data were analyzed separately by sex, viral condition, and treatment with a 2-way RM ANOVA [factors: Time (repeated measure), Chamber].
Both surgery naïve (Experiment 1) and mCherry-expressing female and male B6 mice condition similarly to an intoxicating dose of ethanol and CNO did not interfere with ethanol CPP in the absence of DREADDs. Experiment 2 revealed that NAcC chemogenetic stimulation prevented ethanol CPP in males, while NAcC chemogenetic inhibition prevented ethanol CPP in females.
NAcC chemogenetic manipulations alter ethanol reward differently in male and female B6 mice. Together with prior work, we demonstrate that NAcC activity has a sex-specific role during ethanol reward and consumption. Evidence of sex differences in ethanol reward may help future research to uncover the mechanisms underlying the "telescoping effect" and why women have an increased risk for developing an AUD.
女性从最初饮酒发展到酒精依赖的速度往往比男性更快，这一现象被称为“ telescoping效应”。这表明早期饮酒会产生不同的后果，可能会影响酒精使用障碍（AUD）的发展。先前的证据表明，伏隔核核心（NAcC）的化学遗传学操作对暴饮暴食样饮酒产生相反的影响[刺激会减少C57BL / 6J（B6）雌性小鼠的乙醇摄入量，而抑制作用会减少雄性小鼠的摄入量]。在人类中，乙醇线索条件作用与酒精摄入和中毒的积极主观效应有关。我们测试了这样一个假设，即对NAcC活性进行化学遗传学操作会以性别特异性方式改变乙醇奖赏（通过条件性位置偏爱，CPP来衡量）。
在实验1中，未接受过手术的B6小鼠（每组性别/处理n = 11 - 12只）接受乙醇CPP实验方案，并在乙醇（2 g / kg）条件训练前给予仅由设计药物激活的设计受体（DREADD）激动剂氯氮平 - N - 氧化物（CNO，1 mg / kg）或赋形剂。在实验2中，B6小鼠接受手术，将对照（mCherry）、兴奋性（hM3Dq）或抑制性（hM4Di）DREADD导入NAcC（每组性别/处理n = 8 - 13只）。恢复后，小鼠像在实验1中一样接受乙醇CPP实验。CPP实验在三室装置中进行。在预测试（条件训练前）和测试（4次乙醇和4次生理盐水条件训练后）期间记录小鼠在每个室中花费的时间。数据按性别、病毒条件和处理分别进行分析，采用双向重复测量方差分析[因素：时间（重复测量）、室]。
未接受过手术的（实验1）以及表达mCherry的雌性和雄性B6小鼠对中毒剂量的乙醇的条件反应相似，并且在没有DREADD的情况下，CNO不会干扰乙醇CPP。实验2表明，NAcC化学遗传学刺激可阻止雄性小鼠产生乙醇CPP，而NAcC化学遗传学抑制可阻止雌性小鼠产生乙醇CPP。
NAcC化学遗传学操作在雄性和雌性B6小鼠中对乙醇奖赏的影响不同。结合先前的研究工作，我们证明NAcC活性在乙醇奖赏和消费过程中具有性别特异性作用。乙醇奖赏中性别差异的证据可能有助于未来的研究揭示“ telescoping效应”的潜在机制以及为什么女性患AUD的风险增加。
