There is much interest in identifying novel pharmacotherapeutic targets that improve clinical outcomes for the treatment of alcohol use disorder (AUD). One promising target for therapeutic intervention is the relaxin family peptide 3 (RXFP3) receptor, a cognate receptor for neuropeptide relaxin-3, which has previously been implicated in regulating alcohol drinking behavior. Recently, we developed the first small-molecule RXFP3-selective negative allosteric modulator (NAM) RLX-33. Therefore, the goal of the present work was to characterize the impact of this novel NAM on affective-related behaviors and alcohol self-administration in rats. First, the effects of RLX-33 were tested on alcohol and sucrose self-administration in Wistar and alcohol-preferring P rats to determine the dose–response profile and specificity for alcohol. Then, we assessed the effects of systemic RLX-33 injection in Wistar rats in a battery of behavioral assays (open-field test, elevated zero maze, acoustic startle response test, and prepulse inhibition) and tested for alcohol clearance. We found that the lowest effective dose (5 mg/kg) reduced alcohol self-administration in both male and female Wistar rats, while in alcohol-preferring P rats, this effect was restricted to males, and there were no effects on sucrose self-administration or general locomotor activity. The characterization of affective and metabolic effects in Wistar rats generally found few locomotor, affective, or alcohol clearance changes, particularly at the 5 mg/kg dose. Overall, these findings are promising and suggest that RXFP3 NAM has potential as a pharmacological target for treating AUD.

中文翻译：

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新型 RXFP3 负变构调节剂 RLX-33 减少大鼠自我饮酒


人们对确定可改善酒精使用障碍（AUD）治疗临床结果的新型药物治疗靶点非常感兴趣。治疗干预的一个有希望的目标是松弛素家族肽 3 (RXFP3) 受体，它是神经肽松弛素 3 的同源受体，此前曾被认为与调节饮酒行为有关。最近，我们开发了第一个小分子RXFP3选择性负变构调节剂（NAM）RLX-33。因此，本工作的目标是表征这种新型 NAM 对大鼠情感相关行为和酒精自我管理的影响。首先，在 Wistar 和偏好酒精的 P 大鼠中测试 RLX-33 对酒精和蔗糖自我给药的影响，以确定酒精的剂量反应曲线和特异性。然后，我们通过一系列行为测定（旷场测试、高架零迷宫、声惊吓反应测试和前脉冲抑制）评估了 Wistar 大鼠全身注射 RLX-33 的效果，并测试了酒精清除率。我们发现，最低有效剂量（5 mg/kg）可减少雄性和雌性 Wistar 大鼠的酒精自我给药，而在偏好酒精的 P 大鼠中，这种效应仅限于雄性，并且对蔗糖自我给药没有影响。管理或一般运动活动。 Wistar 大鼠的情感和代谢效应特征通常发现运动、情感或酒精清除率很少发生变化，特别是在 5 mg/kg 剂量下。总体而言，这些发现很有希望，表明 RXFP3 NAM 有潜力作为治疗 AUD 的药理学靶点。