Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats
Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats
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DOI：
10.1016/j.phrs.2020.105357
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发表时间：
2021-02-02
影响因子：
9.3
通讯作者：
Micale, Vincenzo
中科院分区：
文献类型：
--
作者：
Di Bartolomeo, Martina;Stark, Tibor;Micale, Vincenzo
围产期接触Δ⁹ - 四氢大麻酚（THC）会影响大脑发育，并可能增加日后患精神疾病的几率，这似乎与内源性大麻素和/或多巴胺能系统的失调有关。在此，我们评估了围产期接触THC（pTHC）的雄性大鼠中编码大麻素CB1受体（Cnr1）和多巴胺D2受体（Drd2）的基因的转录调控，重点关注通过焦磷酸测序分析的DNA甲基化的作用。同时，评估了在两个不同时间点（即新生期和成年期）的分子和行为异常，以及青春期前用大麻二酚（大麻的一种非致欣快成分）治疗的潜在预防效果。还在一组精神分裂症患者中评估了DRD2甲基化情况。我们观察到，在成年期接触pTHC的大鼠的前额叶皮质中，Cnr1和Drd2的mRNA水平均选择性升高，同时Drd2调控区域的DNA甲基化持续降低，伴有社交退缩和认知障碍，而大麻二酚治疗可逆转这些情况。在新生期，这些成年期的异常之前表现为新生儿反射出现延迟、Drd2 mRNA水平升高以及大脑中2 - 花生四烯酰甘油（2 - AG）水平降低，这些情况一直持续到成年期。在精神分裂症患者中也发现了DRD2的表观遗传标记的改变。总体而言，所报道的数据为多巴胺 - 大麻素相互作用在DRD2和CNR1失调方面提供了进一步的证据，这可能与精神分裂症谱系障碍的发病机制有关，表明大麻二酚治疗可能通过调节改变的多巴胺能活性使pTHC诱导的精神病理学恢复正常。
Perinatal exposure to Delta(9)-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.