Many of the behavioral symptoms that define alcohol use disorder (AUD) are thought to be mediated by amplified glutamatergic activity. As a result, previous preclinical studies have investigated glutamate receptor inhibition as a potential pharmacotherapy for AUD, particularly the metabotropic glutamate receptor 5 (mGlu5). In rodents, mGlu5 negative allosteric modulators (NAMs) have been shown to decrease alcohol self-administration. However, their effect on non-human primates has not previously been explored. To bridge this gap, the effects of mGlu5 NAM pretreatment on sweetened alcohol (8% w/v in diluted KoolAid) self-administration in female baboons were evaluated. Two different mGlu5 NAMs were tested: 1) 3-2((-Methyl-4-thiazolyl) ethynyl) pyridine (MTEP) which was administered at a dose of 2 mg/kg IM; and 2) auglurant (N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide), a newly developed NAM, which was tested under two different routes (0.001, 0.01, 0.03, 0.1 mg/kg IM and 0.1, 0.3, 1.0 mg/kg PO). MTEP decreased both fixed ratio and progressive ratio responding for sweetened alcohol. Auglurant, administered IM, decreased alcohol self-administration at doses that did not affect self-administration of an alcohol-free sweet liquid reward (0.01 to 0.1 mg/kg). Oral administration of auglurant was not effective in decreasing alcohol self-administration. Our results extend positive findings from rodent studies on mGlu5 regulation of alcohol drinking to female baboons and further strengthen the rationale for targeting mGlu5 in clinical trials for AUD.

许多定义酒精使用障碍 (AUD) 的行为症状被认为是由放大的谷氨酸能活动介导的。因此，之前的临床前研究已经研究了谷氨酸受体抑制作为 AUD 的潜在药物疗法，特别是代谢型谷氨酸受体 5 (mGlu5)。在啮齿动物中，mGlu5 负变构调节剂 (NAM) 已被证明可以减少酒精的自我管理。然而，它们对非人类灵长类动物的影响以前没有被探索过。为了弥合这一差距，评估了 mGlu5 NAM 预处理对雌性狒狒自我给药加糖酒精（稀释的 KoolAid 中的 8% w/v）的影响。测试了两种不同的 mGlu5 NAM：1) 3-2((-Methyl-4-thiazolyl) ethynyl) pyridine (MTEP)，以 2 mg/kg IM 的剂量给药；和 2) 助剂 (N -(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide), 一种新开发的 NAM, 在两种不同的途径下进行了测试 (0.001, 0.01, 0.03, 0.1 mg/公斤肌注和 0.1、0.3、1.0 毫克/公斤口服）。MTEP 降低了固定比例和渐进比例对甜酒的反应。Auglurant，IM 给药，在不影响无酒精甜液体奖励（0.01 至 0.1 mg/kg）自我给药的剂量下减少酒精自我给药。口服 auglurant 在减少酒精自我管理方面无效。我们的结果将啮齿动物研究中关于 mGlu5 调节饮酒的积极发现扩展到雌性狒狒，并进一步加强了在 AUD 临床试验中靶向 mGlu5 的基本原理。