School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
Neuropsychopharmacology. 2021 Nov;46(12):2121-2131. doi: 10.1038/s41386-021-01096-1. Epub 2021 Jul 20.
In patients suffering from alcohol use disorder (AUD), stress and environmental stimuli associated with alcohol availability are important triggers of relapse. Activation of the nociceptin opioid peptide (NOP) receptor by its endogenous ligand Nociceptin/Orphanin FQ (N/OFQ) attenuates alcohol drinking and relapse in rodents, suggesting that NOP agonists may be efficacious in treating AUD. Intriguingly, recent data demonstrated that also blockade of NOP receptor reduced alcohol drinking in rodents. To explore further the potential of NOP antagonism, we investigated its effects on the reinstatement of alcohol-seeking elicited by administration of the α2 antagonist yohimbine (1.25 mg/kg, i.p.) or by environmental conditioning factors in male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The selective NOP receptor antagonist LY2817412 (0.0, 3.0, 10.0, and 30.0 mg/kg) was first tested following oral (p.o.) administration. We then investigated the effects of LY2817412 (1.0, 3.0, 6.0 μg/μl/rat) microinjected into three candidate mesolimbic brain regions: the ventral tegmental area (VTA), the central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc). We found that relapse to alcohol seeking was generally stronger in female than in male rats and oral administration of LY2817412 reduced yohimbine- and cue-induced reinstatement in both sexes. Following site-specific microinjections, LY2817412 reduced yohimbine-induced reinstatement of alcohol-seeking when administered into the VTA and the CeA, but not in the NAc. Cue-induced reinstatement was suppressed only when LY2817412 was microinjected into the VTA. Infusions of LY2817412 into the VTA and the CeA did not alter saccharin self-administration. These results demonstrate that NOP receptor blockade prevents the reinstatement of alcohol-seeking through modulation of mesolimbic system circuitry, providing further evidence of the therapeutic potential of NOP receptor antagonism in AUD.
在患有酒精使用障碍（AUD）的患者中，与酒精可用性相关的压力和环境刺激是复发的重要诱因。内源性配体孤啡肽/孤啡肽 FQ（N/OFQ）激活阿片肽（NOP）受体可减轻啮齿动物的饮酒和复发，表明 NOP 激动剂可能有效治疗 AUD。有趣的是，最近的数据表明，NOP 受体阻断也可减少啮齿动物的饮酒量。为了进一步探索 NOP 拮抗作用的潜力，我们研究了其对雄性和雌性遗传选择的酒精偏好的 Marchigian Sardinian（msP）大鼠给予α2 拮抗剂育亨宾（1.25mg/kg，ip）或环境条件因素给药后觅酒行为复燃的影响。首先经口（p.o.）给予选择性 NOP 受体拮抗剂 LY2817412（0.0、3.0、10.0 和 30.0mg/kg）进行测试。然后，我们研究了 LY2817412（1.0、3.0、6.0μg/μl/大鼠）微注射到三个候选的中脑边缘脑区的效果：腹侧被盖区（VTA）、杏仁中央核（CeA）和伏隔核（NAc）。我们发现，女性大鼠的觅酒行为复燃一般强于男性大鼠，经口给予 LY2817412 可减少两性的育亨宾和线索诱导的复燃。进行特定部位的微注射后，当 LY2817412 注入 VTA 和 CeA 时，它可减少育亨宾诱导的觅酒行为复燃，但在 NAc 中则不然。当 LY2817412 微注射到 VTA 时，线索诱导的复燃受到抑制。LY2817412 注入 VTA 和 CeA 不会改变蔗糖的自我给药。这些结果表明，NOP 受体阻断通过调节中脑边缘系统回路来防止觅酒行为的复燃，为 NOP 受体拮抗作用在 AUD 中的治疗潜力提供了进一步的证据。
