Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, Georgia; Yerkes National Primate Research Center, The Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia; Department of Pediatrics, Emory School of Medicine, Emory University, Atlanta, Georgia.
Graduate Program in Neuroscience, Emory University, Atlanta, Georgia; Yerkes National Primate Research Center, The Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia; Department of Pediatrics, Emory School of Medicine, Emory University, Atlanta, Georgia.
Biol Psychiatry. 2021 May 15;89(10):959-969. doi: 10.1016/j.biopsych.2021.01.008. Epub 2021 Jan 27.
The PI3-kinase (PI3K) complex is a well-validated target for mitigating cocaine-elicited sequelae, but pan-PI3K inhibitors are not viable long-term treatment options. The PI3K complex is composed of p110 catalytic and regulatory subunits, which can be individually manipulated for therapeutic purposes. However, this possibility has largely not been explored in behavioral contexts.
Here, we inhibited PI3K p110β in the medial prefrontal cortex (mPFC) of cocaine-exposed mice. Behavioral models for studying relapse, sensitization, and decision-making biases were paired with protein quantification, RNA sequencing, and cell type-specific chemogenetic manipulation and RNA quantification to determine whether and how inhibiting PI3K p110β confers resilience to cocaine.
Viral-mediated PI3K p110β silencing reduced cue-induced reinstatement of cocaine seeking by half, blocked locomotor sensitization, and restored mPFC synaptic marker content after exposure to cocaine. Cocaine blocked the ability of mice to select actions based on their consequences, and p110β inhibition restored this ability. Silencing dopamine D receptor-expressing excitatory mPFC neurons mimicked cocaine, impairing goal-seeking behavior, and again, p110β inhibition restored goal-oriented action. We verified the presence of p110β in mPFC neurons projecting to the dorsal striatum and orbitofrontal cortex and found that inhibiting p110β in the mPFC altered the expression of functionally defined gene clusters within the dorsal striatum and not orbitofrontal cortex.
Subunit-selective PI3K silencing potently mitigates drug seeking, sensitization, and decision-making biases after exposure to cocaine. We suggest that inhibiting PI3K p110β provides neuroprotection against cocaine by triggering coordinated corticostriatal adaptations.
PI3-激酶（PI3K）复合物是减轻可卡因引起的后遗症的一个经过充分验证的靶点，但泛 PI3K 抑制剂不是可行的长期治疗选择。PI3K 复合物由 p110 催化亚基和调节亚基组成，可单独用于治疗目的。然而，这种可能性在行为背景下基本上没有被探索过。
在这里，我们抑制了可卡因暴露小鼠内侧前额叶皮层（mPFC）中的 PI3K p110β。用于研究复发、敏化和决策偏差的行为模型与蛋白质定量、RNA 测序以及细胞类型特异性化学遗传操作和 RNA 定量配对，以确定抑制 PI3K p110β是否以及如何赋予可卡因的抗性。
病毒介导的 PI3K p110β 沉默将线索诱导的可卡因寻求复燃减少了一半，阻断了运动敏化，并在暴露于可卡因后恢复了 mPFC 突触标记物的含量。可卡因阻止了老鼠根据后果选择行动的能力，而 p110β 抑制恢复了这种能力。沉默多巴胺 D 受体表达的兴奋性 mPFC 神经元模拟可卡因，损害了目标寻求行为，而再次，p110β 抑制恢复了目标导向的行动。我们验证了投射到背侧纹状体和眶额皮层的 mPFC 神经元中存在 p110β，并发现抑制 mPFC 中的 p110β改变了背侧纹状体而非眶额皮层内功能定义基因簇的表达。
亚单位选择性 PI3K 沉默强烈减轻了暴露于可卡因后的觅药、敏化和决策偏差。我们认为，通过触发皮质纹状体的协调适应，抑制 PI3K p110β 为可卡因提供神经保护。
