Department of Addictology, First Faculty of Medicine, Charles University, Apolinarska 4, 128 00 Prague 2, Czech Republic.
Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, 100 34 Prague 10, Czech Republic.
Int J Mol Sci. 2020 Dec 28;22(1):210. doi: 10.3390/ijms22010210.
The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2-induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.
内源性大麻素/CB1R 系统以及生长激素促分泌受体（GHS-R1A）的中央促胃激素信号传导系统在食物摄入和奖励/强化处理中起着重要作用，并且在包括下丘脑（食物摄入）、腹侧被盖区（VTA）和伏隔核（NAC）（奖励/强化）在内的相关脑区的分布中存在明显的重叠。这些系统在食物摄入方面的相互作用已经得到了充分的证明；然而，促胃激素/ GHS-R1A 在大麻素强化效应和成瘾中的作用尚不清楚。因此，本研究的主要目的是研究 GHS-R1A 拮抗剂/JMV2959 预处理是否可以减少 CB1R 激动剂/WIN55,212-2 在伏隔核壳（NACSh）中的多巴胺释放，这被认为是成瘾过程的关键触发冲动。将合成的氨基酸烷基吲哚大麻素 WIN55,212-2 注入 VTA 后，会显著诱导伏隔核多巴胺的释放，而 3mg/kg 的 JMV2959 预处理则显著减少了这一反应。同时，JMV2959 预处理也显著增加了大麻素引起的伏隔核多巴胺代谢周转率。脑室内 WIN55,212-2 的给药也增加了 NACSh 中的内源性大麻素花生四烯酰乙醇胺/大麻二酚和 2-花生四烯酰甘油/2-AG 的细胞外水平，JMV2959 预处理可适度但显著减弱这种作用。此外，JMV2959 预处理还逆转了大麻素引起的伏隔核γ-氨基丁酸/γ-氨基丁酸水平的降低。在 LABORAS 笼中的行为研究表明，3mg/kg 的 JMV2959 预处理也显著减少了全身 WIN55,212-2 引起的行为刺激。我们的结果表明，促胃激素/ GHS-R1A 系统显著参与了大麻素/CB1 激动剂的奖赏/强化作用，而这些作用与大麻素成瘾处理有关。
