Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague 10, Czech Republic.
Department of Addictology, First Faculty of Medicine, Charles University, Apolinarska 4, 128 00 Prague 2, Czech Republic.
Int J Mol Sci. 2021 Feb 27;22(5):2397. doi: 10.3390/ijms22052397.
Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.
大麻/大麻素被广泛用于娱乐和治疗目的，但它们的风险在很大程度上被忽视了。然而，大麻素相关的使用障碍和依赖正在惊人地增加，而有效的治疗方法却缺乏。最近，生长激素促分泌素受体（GHSR1A）拮抗作用被提出作为一种有前途的药物成瘾治疗机制。然而，GHS-R1A 及其内源性配体 ghrelin 在大麻素滥用中的作用尚不清楚。因此，我们的研究目的是调查 GHS-R1A 拮抗剂 JMV2959 是否能减少四氢大麻酚（THC）诱导的条件性位置偏爱（CPP）和行为刺激、WIN55,212-2 静脉自我给药（IVSA）以及复发的倾向。在持续的 WIN55,212-2 自我给药后，JMV2959 3mg/kg 于三个连续的 120 分钟 IVSA 疗程前 20 分钟腹腔内给药，在固定比率 FR1 下，这显著减少了主动杠杆按压的次数、注射次数和大麻素的摄入量。JMV2959 的预处理提示在强制戒断期的第 12 天，大鼠对 WIN55,212-2 的觅药/复发样行为减少。相反，ghrelin 的预处理显著增加了大麻素的 IVSA，并增强了复发样行为。ghrelin 与 JMV2959 共同给药消除/减少了 GHS-R1A 拮抗剂在大麻素 IVSA 中的显著疗效。JMV2959 预处理显著且剂量依赖性地降低了 THC 诱导的 CPP 的表现。在条件作用过程中同时给予 JMV2959 和 THC 后，THC-CPP 的发展减少。JMV2959 还显著减少了 LABORAS 笼中 THC 诱导的行为刺激。我们的研究结果表明，GHS-R1A 重要参与大麻素的奖赏/强化作用。
