PDF(Sci-hub)
Abstract：
Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.
摘要：
皮质回路功能障碍被认为是精神分裂症（SZ）病理生理学的潜在机制，异常回路活性的正常化被提议作为抗精神病药效的生物标志物。大麻二酚（CBD）显示出作为辅助抗精神病治疗的潜力;然而，这些药物相互作用中潜在的性别效应仍然未知.在本研究中,我们试图阐明CBD与非典型抗精神病药物伊潘立酮(ILO)联合给药对用于SZ研究的大鼠甲基唑氧甲醇醋酸酯(MAM)模型来源的原代皮质神经元培养物活性的性别效应.在基线和单独施用CBD或ILO后，使用多电极阵列获得自发网络活动测量，或组合。在基线,与性别匹配的对照相比，MAM男性神经元的爆发活性增加，而MAM女性神经元的爆发活性没有差异。单独施用的CBD显示了MAM网络中神经元活性的快速但短暂的增加，在女性中更明显的效果。此外，ILO对CBD诱导的MAM雄性神经元活性升高具有累加作用。在MAM女性神经元中，CBD或ILO给药导致神经元活动的时间依赖性升高，但是当CBD和ILO合并时，短期CBD诱导的活性增加就消失了。我们的发现表明，CBD诱导皮质神经元活动的快速增加，与国际劳工组织共同管理时的性别特异性药物相互作用。这表明，在实施用于治疗SZ的辅助疗法时，应考虑性别。
