Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina, USA.
J Neurochem. 2023 Oct;167(2):204-217. doi: 10.1111/jnc.15949. Epub 2023 Sep 6.
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.
人们对确定新的药物治疗靶点以改善酒精使用障碍 (AUD) 的治疗效果非常感兴趣。一个有前途的治疗干预靶点是松弛素家族肽 3 (RXFP3) 受体，它是神经肽松弛素-3 的同源受体，先前已被证明与调节酒精摄入行为有关。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，本工作的目标是研究这种新型 NAM 对大鼠情感相关行为和酒精自我给药的影响。首先，在 Wistar 和酒精偏好 P 大鼠中测试 RLX-33 对酒精和蔗糖自我给药的影响，以确定剂量反应曲线和对酒精的特异性。然后，我们评估了系统给予 RLX-33 在 Wistar 大鼠一系列行为测试（旷场测试、高架零迷宫、听觉惊跳反应测试和条件性恐惧抑制）中的影响，并测试了酒精清除率。我们发现，最低有效剂量（5mg/kg）减少了雄性和雌性 Wistar 大鼠的酒精自我给药，而在酒精偏好 P 大鼠中，这种作用仅限于雄性，对蔗糖自我给药或一般运动活动没有影响。Wistar 大鼠情感和代谢效应的特征通常发现运动、情感或酒精清除率变化很少，特别是在 5mg/kg 剂量下。总的来说，这些发现很有希望，表明 RXFP3 NAM 有潜力成为治疗 AUD 的药物靶点。
