Department of Cell Biology and Anatomy, Lousiana State University Health Sciences Center, New Orleans, LA, USA.
Departments of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA.
Pharmacol Biochem Behav. 2021 Sep;208:173227. doi: 10.1016/j.pbb.2021.173227. Epub 2021 Jul 2.
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，以前的临床前研究已经研究了谷氨酸受体抑制作为 AUD 的一种潜在药物治疗方法，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）已被证明可减少酒精自我给药。然而，它们对非人类灵长类动物的影响以前尚未被探索过。为了弥补这一空白，评估了 mGlu5 NAM 预处理对雌性狒狒加糖酒精（8%w/v 在稀释的酷乐中）自我给药的影响。测试了两种不同的 mGlu5 NAM：1）3-2-((-甲基-4-噻唑基)乙炔基)吡啶（MTEP），其以 2mg/kg IM 的剂量给药；2）新开发的 NAM auglurant（N-(5-氟吡啶-2-基)-6-甲基-4-(嘧啶-5-氧基)吡啶甲酰胺），以两种不同途径（0.001、0.01、0.03、0.1mg/kg IM 和 0.1、0.3、1.0mg/kg PO）进行测试。MTEP 降低了加糖酒精的固定比率和递增比率反应。在不影响无酒精甜味液奖励的自我给药的剂量下，IM 给予 auglurant 可降低酒精的自我给药。奥格卢兰的口服给药不能有效减少酒精的自我给药。我们的结果将 mGlu5 调节酒精摄入的啮齿动物研究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 的合理性。
