Inhibiting P13K p110B to block cocaine-induced habits and drug seeking

抑制 P13K p110B 以阻止可卡因诱发的习惯和药物寻求

• 批准号: 10318954
• 负责人: Shannon Leigh Gourley
• 金额: $ 39.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318954
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adolescence; Adolescent; Adult; Anatomy; Behavior; Behavioral; Catalytic Domain; Clinical; Cocaine; Complex; Corpus striatum structure; Coupled; Crystallization; Decision Making; Dendritic Spines; Development; Disinhibition; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug Experimentation; Drug Use Disorder; Environment; Exposure to; FRAP1 gene; Family; Fragile X Syndrome; Gene Silencing; Goals; Guanosine Triphosphate Phosphohydrolases; Habits; Human; Individual; Infusion procedures; Intraventricular; Knowledge; Learning; Life; Long-Term Depression; Medial; Mediating; Membrane; Memory; Modeling; Morphology; N-Methyl-D-Aspartate Receptors; Nature; Neurobiology; Neurons; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Phosphatidylinositols; Prefrontal Cortex; Reporting; Second Messenger Systems; Signal Transduction; Site; Stimulus; Structure; Sum; System; Techniques; Testing; Viral; base; cell type; cocaine exposure; density; drug of abuse; excitatory neuron; experimental study; inhibitor; knock-down; neuron development; novel strategies; overexpression; postnatal development; psychostimulant; receptor; receptor-mediated signaling; resilience; response; treatment strategy; young adult

SUMMARY PI3-kinase (PI3K) is a membrane-associated signaling complex that phosphorylates phosphoinositides, second messengers that regulate neuronal development, survival, and plasticity. In 2002, Izzo et al. reported that intraventricular PI3K inhibition blocks the expression of cocaine-induced psychomotor sensitization (Nature Neurosci.). Subsequent studies indicated that repeated cocaine exposure can increase PI3K activity in the medial prefrontal cortex (mPFC). Nevertheless, causal relationships between mPFC PI3K and cocaine- induced behavioral sequelae remain unconfirmed. We will directly manipulate the PI3K subunit p110β to mitigate stimulus-elicited habits following cocaine. p110β is one of the four PI3K catalytic subunits, and it is highly expressed throughout postnatal development and in adulthood. We find that reduction of Pik3cb, encoding p110β, broadly throughout the mPFC blocks stimulus-elicited habits and locomotor sensitization following cocaine exposure during adolescence or young adulthood. These are periods of considerable drug experimentation in humans. In Aim 1, we will use viral-mediated gene silencing to identify specific mPFC subregions responsible for the “protective” consequences of Pik3cb inhibition. One widely-reported consequence of repeated cocaine exposure is an imbalance in dopamine receptor- mediated signaling, favoring D1-family Gs-coupled, at the expense of D2-family Gi-coupled, systems. D1 stimulation activates PI3K and is a likely mechanism by which psychostimulants strengthen habit-based behavior. Overexpression of Drd1 in the mPFC decreases D2 expression in the downstream striatum, suggesting that normalization of mPFC D1-mediated signaling following cocaine could engage striatal D2 systems. In Aim 2, we will test the hypothesis that Pik3cb inhibition in the mPFC creates a permissive environment for dorsomedial striatal D2-dependent goal-directed response strategies. Cocaine can induce activity-dependent dendritic spine proliferation in the mPFC. Meanwhile, inhibiting PI3K p110β can normalize aberrant dendritic spine proliferation in models of Fragile X Syndrome. Thus, inhibiting p110β could conceivably correct cocaine-induced spinogenesis. Further, PI3K p110δ and γ regulate RhoA GTPase-dependent neuronal contraction and NMDA receptor-dependent long-term depression, respectively. In Aim 3, we will test the hypothesis that inhibiting p110β and δ will correct dendritic spine densities and block habits following cocaine, while p110γ inhibition could exacerbate cocaine’s influence. Our findings indicate that p110β blockade confers certain behavioral resiliencies to cocaine. The proposed studies will crystallize anatomical mechanisms and cyto-structural consequences. Knowledge gained from these experiments could advance treatment strategies for drug use disorders, given that subunit-selective inhibitors may have more favorable clinical profiles than broad-spectrum PI3K blockade.

概括 PI3-激酶 (PI3K) 是一种膜相关信号复合物，可磷酸化磷酸肌醇， 调节神经元发育、存活和可塑性的第二信使。 2002 年，伊佐等人。报道 心室内 PI3K 抑制可阻断可卡因诱导的精神运动敏化的表达 （自然神经科学）。随后的研究表明，反复接触可卡因可以增加 PI3K 活性 内侧前额皮质 (mPFC)。然而，mPFC PI3K 与可卡因之间的因果关系 诱发的行为后遗症尚未得到证实。我们将直接操纵 PI3K 亚基 p110β 来 减轻可卡因刺激引起的习惯。 p110β 是 PI3K 四个催化亚基之一，在出生后的整个过程中高度表达 发育和成年期。我们发现编码 p110β 的 Pik3cb 的减少广泛存在于整个 mPFC 可阻止可卡因暴露后的刺激引起的习惯和运动敏化 青春期或成年初期。这是在人体上进行大量药物实验的时期。瞄准 1，我们将使用病毒介导的基因沉默来识别负责的特定 mPFC 亚区 Pik3cb 抑制的“保护性”后果。 反复接触可卡因的一个广泛报道的后果是多巴胺受体失衡 介导的信号传导，有利于 D1 家族 Gs 偶联，但牺牲了 D2 家族 Gi 偶联系统。 D1 刺激激活 PI3K，并且是精神兴奋剂增强基于习惯的可能机制。 行为。 mPFC 中 Drd1 的过度表达会降低下游纹状体中 D2 的表达， 表明可卡因后 mPFC D1 介导的信号正常化可能会参与纹状体 D2 系统。在目标 2 中，我们将检验以下假设：mPFC 中的 Pik3cb 抑制会产生许可性 背内侧纹状体 D2 依赖性目标导向反应策略的环境。 可卡因可以诱导 mPFC 中活性依赖性树突棘增殖。同时，抑制 PI3K p110β 可以使脆性 X 综合征模型中异常的树突棘增殖正常化。因此， 抑制 p110β 可能可以纠正可卡因诱导的脊柱形成。此外，PI3K p110δ 和 γ 调节 RhoA GTPase 依赖性神经元收缩和 NMDA 受体依赖性长期抑制， 分别。在目标 3 中，我们将测试抑制 p110β 和 δ 将纠正树突棘的假设 密度并阻止可卡因的习惯，而 p110γ 抑制可能会加剧可卡因的影响。 我们的研究结果表明，p110β 阻断赋予可卡因一定的行为弹性。拟议的 研究将明确解剖机制和细胞结构后果。获得的知识来自 鉴于亚单位选择性，这些实验可以推进吸毒障碍的治疗策略 抑制剂可能比广谱 PI3K 阻断剂具有更有利的临床特征。