Available pharmacotherapies to treat alcohol use disorder (AUD) show limited efficacy. Preclinical studies in mice and rats suggested that antagonists of the corticotropin releasing factor receptor 1 (CRFR1) could be more efficacious for such treatment. However, clinical trials with CRFR1 antagonists were not successful. While a number of potential explanations for this translational failure have been suggested, we hypothesized that the lack of success in clinical trials could be in part due to different neuroanatomical organization of the CRFR1 system in mice and rats versus humans. The CRF system in prairie voles (Microtus ochrogaster), a socially monogamous rodent species, also shows differences in organization from mice and rats. To test our hypothesis, we compared the efficacy of a potent CRFR1 antagonist, CP-376,395, to modulate alcohol drinking in male and female prairie voles versus male and female C57BL/6J mice using an almost identical 2-bottle choice drinking procedure. CP-376,375 (10 and 20 mg/kg, i.p.) significantly decreased alcohol intake (but not alcohol preference) in mice, but not prairie voles. Furthermore, administration of this antagonist (20 mg/kg, i.p.) prior to the partner preference test (PPT) decreased partner preference (PP) in male prairie voles. These findings support our hypothesis that the greater efficacy of CRFR1 antagonists to suppress alcohol consumption in mice and rats versus other mammalian species could be due to the differences in organization of the CRFR1 system between species. They further indicate that activity of the CRFR1 system is necessary for the formation of pair-bonds, but not consumption of high doses of alcohol. Overall, we suggest that testing potential pharmacotherapies should not rely only on studies in mice and rats.

中文翻译：

---

草原田鼠和小鼠的饮酒差异敏感性和伴侣对CRFR1拮抗剂的偏爱。

现有的治疗酒精使用障碍（AUD）的药物疗法显示出有限的疗效。在小鼠和大鼠中的临床前研究表明，促肾上腺皮质激素释放因子受体1（CRFR1）的拮抗剂可能更有效。但是，CRFR1拮抗剂的临床试验并不成功。尽管已经提出了许多有关这种翻译失败的潜在解释，但我们假设临床试验中缺乏成功的部分原因可能是小鼠和大鼠与人的CRFR1系统的神经解剖结构不同。社会一夫一妻制啮齿动物草原田鼠（田鼠（Microtus ochrogaster））的CRF系统也显示出小鼠和大鼠的组织差异。为了检验我们的假设，我们比较了有效的CRFR1拮抗剂CP-376,395，使用几乎相同的2瓶选择饮酒程序来调节雄性和雌性草原田鼠与雄性和雌性C57BL / 6J小鼠的饮酒。CP-376,375（10和20 mg / kg，腹腔注射）可显着降低小鼠的酒精摄入（但不降低酒精偏好），但不降低草原田鼠的酒精摄入。此外，在雄性大田鼠中，在伴侣偏好测试（PPT）之前给予这种拮抗剂（20 mg / kg，ip）会降低伴侣偏好（PP）。这些发现支持了我们的假设，即CRFR1拮抗剂与其他哺乳动物相比，抑制小鼠和大鼠饮酒的更大功效可能是由于不同物种之间CRFR1系统组织的差异。他们进一步表明，CRFR1系统的活性对于成对键的形成是必需的，但不是消耗高剂量的酒精。