Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
Neuropsychopharmacology. 2021 Sep;46(10):1734-1745. doi: 10.1038/s41386-021-01028-z. Epub 2021 May 19.
Opioid-based drugs are frequently used for pain management in both males and females despite the known risk of prefrontal cortex dysfunction and cognitive impairments. Although poorly understood, loss of cognitive control following chronic drug use has been linked to decreased activation of frontal cortex regions. Here, we show that self-administration of the potent opioid, remifentanil, causes a long-lasting hypoactive basal state evidenced by a decrease in ex vivo excitability that is paralleled by an increase in firing capacity of layer 5/6 pyramidal neurons in the prelimbic, but not infralimbic region of the medial prefrontal cortex. This phenomenon was observed in females after as few as 5 days and up to 25-30 days of self-administration. In contrast, pyramidal neurons in males showed increased excitability following 10-16 days of self-administration, with hypoactive states arising only following 25-30 days of self-administration. The emergence of a hypoactive, but not hyperactive basal state following remifentanil self-administration aligned with deficits in cognitive flexibility as assessed using an operant-based attentional set-shifting task. In females, the hypoactive basal state is driven by a reduction in excitatory synaptic transmission mediated by AMPA-type glutamate receptors. Alternatively, hyper- and hypoactive states in males align selectively with decreased and increased GABA signaling, respectively. Chemogenetic compensation for this hypoactive state prior to testing restored cognitive flexibility, basal hypoactive state, and remifentanil-induced plasticity. These data define cellular and synaptic mechanisms by which opioids impair prefrontal function and cognitive control; indicating that interventions aimed at targeting opioid-induced adaptations should be tailored based on biological sex.
尽管已知阿片类药物会导致前额叶皮层功能障碍和认知损伤，但它们仍被频繁用于男性和女性的疼痛管理。尽管了解甚少，但慢性药物使用后认知控制的丧失与额叶皮层区域激活减少有关。在这里，我们表明，强效阿片类药物瑞芬太尼的自我给药会导致持久的基础活动低下，表现在离体兴奋性降低，同时前额叶皮质内侧前扣带皮层的第 5/6 层锥体神经元的放电能力增加。这种现象在女性中仅在自我给药 5 天至多达 25-30 天后观察到。相比之下，雄性中的锥体神经元在自我给药 10-16 天后表现出兴奋性增加，仅在自我给药 25-30 天后才出现基础活动低下。瑞芬太尼自我给药后出现的基础活动低下，但非过度活跃状态与使用操作性注意定势转移任务评估的认知灵活性缺陷一致。在女性中，这种基础活动低下状态是由 AMPA 型谷氨酸受体介导的兴奋性突触传递减少驱动的。相反，雄性中的过度活跃和基础活动低下状态分别与 GABA 信号的减少和增加选择性一致。在测试前进行这种基础活动低下状态的化学遗传补偿恢复了认知灵活性、基础活动低下状态和瑞芬太尼诱导的可塑性。这些数据定义了阿片类药物损害前额叶功能和认知控制的细胞和突触机制；表明针对阿片类药物诱导适应的干预措施应根据生物学性别进行调整。
