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

总结 PI 3-激酶（PI 3 K）是一种膜相关信号复合物，其磷酸化磷酸肌醇， 调节神经元发育、存活和可塑性的第二信使。2002年，Izzo等人报道， 脑室内PI 3 K抑制阻断可卡因诱导的精神敏化的表达， （Nature Neurosci.）随后的研究表明，重复的可卡因暴露可以增加PI 3 K活性， 内侧前额叶皮层（mPFC）。然而，mPFC PI 3 K和可卡因之间的因果关系- 诱发的行为后遗症仍未得到证实。我们将直接操纵PI 3 K亚基p110β， 减轻可卡因后刺激引起的习惯。 p110β是PI 3 K的四个催化亚基之一，在整个出生后高表达 发展和成年。我们发现，Pik 3cb，编码p110β，广泛地在整个 mPFC阻断可卡因暴露后刺激引起的习惯和运动敏感化 青春期或青年期。这是相当多的人类药物实验的时期。在Aim中 1，我们将使用病毒介导的基因沉默，以确定特定的mPFC亚区负责的， Pik 3cb抑制的“保护性”后果。 一个被广泛报道的重复接触可卡因的后果是多巴胺受体的失衡- 介导的信号传导，有利于D1家族GS偶联，以D2家族GI偶联系统为代价。D1 刺激激活PI 3 K，是精神兴奋剂加强习惯性的可能机制。 行为mPFC中Drd 1的过表达降低了下游纹状体中D2的表达， 这表明，可卡因后mPFC D1介导的信号正常化可以使纹状体D2 系统.在目标2中，我们将检验mPFC中的Pik 3cb抑制产生允许的 背内侧纹状体D2依赖性目标导向反应策略的环境。 皮质醇可诱导mPFC中活性依赖性树突棘增殖。同时，抑制 PI 3 K p110β可使脆性X综合征模型中异常树突棘增殖正常化。因此，在本发明中， 抑制p110β可以令人信服地纠正可卡因诱导的脊髓生成。此外，PI 3 K p110δ和γ调节 RhoA GTP酶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，我们将检验抑制p110β和δ将纠正树突棘的假设。 密度和块习惯后可卡因，而p110γ抑制可加重可卡因的影响。 我们的研究结果表明，p110β阻断剂对可卡因具有一定的行为依赖性。拟议 这些研究将使解剖机制和细胞结构后果具体化。获得的消息 这些实验可以推进药物使用障碍的治疗策略，因为亚基选择性 抑制剂可能比广谱PI 3 K阻断剂具有更有利的临床特征。

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.