Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, Sótano, Málaga 29010, Spain.
Programa de Neurociencias, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
Eur Neuropsychopharmacol. 2020 Apr;33:126-138. doi: 10.1016/j.euroneuro.2020.01.012. Epub 2020 Feb 10.
The adolescent brain displays high vulnerability to the deleterious effects of ethanol, including greater risk of developing alcohol use disorder later in life. Here, we characterized the gene expression of the endocannabinoid system (ECS) and relevant signaling systems associated with neuroinflammation and emotional behaviors in the brain of young adult control and ethanol-exposed (EtOH) rats. We measured mRNA levels of candidate genes using quantitative real time PCR in the medial prefrontal cortex (mPFC), amygdala and hippocampus. EtOH rats were generated by maintenance on an intermittent and voluntary ethanol consumption during adolescence using the two-bottle choice paradigm (4 days/week for 4 weeks) followed by 2 week-withdrawal, a time-point of withdrawal with no physical symptoms. Mean differences and effect sizes were calculated using t-test and Cohen's d values. In the mPFC and hippocampus, EtOH rats had significantly higher mRNA expression of endocannabinoid-signaling (mPFC: Ppara, Dagla, Daglb and Napepld; and hippocampus: Cnr2, Dagla and Mgll) and neuroinflammation-associated genes (mPFC: Gfap; and hippocampus: Aif1) than in controls. Moreover, EtOH rats had significantly higher mRNA expression of neuropeptide Y receptor genes (Npy1r, Npy2r and Npy5r) in the hippocampus. Finally, EtOH rats also displayed higher plasma endocannabinoid levels than controls. In conclusion, these results suggest that adolescent ethanol exposure can lead to long-term alterations in the gene expression of the ECS and other signaling systems involved in neuroinflammation and regulation of emotional behaviors in key brain areas for the development of addiction.
青春期大脑对乙醇的有害影响非常敏感，包括日后更易患上酒精使用障碍。在这里，我们描述了内源性大麻素系统（ECS）的基因表达，以及与神经炎症和情绪行为相关的相关信号系统，这些都在年轻成年对照和乙醇暴露（EtOH）大鼠的大脑中。我们使用定量实时 PCR 测量了中前额皮质（mPFC）、杏仁核和海马中候选基因的 mRNA 水平。EtOH 大鼠是通过在青春期使用双瓶选择范式（每周 4 天，持续 4 周）维持间歇性和自愿性乙醇消耗而产生的，随后是 2 周戒断，此时没有身体症状戒断。使用 t 检验和 Cohen 的 d 值计算均值差异和效应大小。在 mPFC 和海马中，EtOH 大鼠的内源性大麻素信号（mPFC：Ppara、Dagla、Daglb 和 Napepld；和海马：Cnr2、Dagla 和 Mgll）和神经炎症相关基因（mPFC：Gfap；和海马：Aif1）的 mRNA 表达明显高于对照组。此外，EtOH 大鼠的海马中神经肽 Y 受体基因（Npy1r、Npy2r 和 Npy5r）的 mRNA 表达明显更高。最后，EtOH 大鼠的血浆内源性大麻素水平也高于对照组。总之，这些结果表明，青春期乙醇暴露会导致 ECS 及其它参与神经炎症和调节情绪行为的信号系统的基因表达发生长期改变，而这些改变是成瘾发展的关键大脑区域的特征。
