Altered Midbrain GABAergic Circuitry Drives Greater Cocaine Self-administration

中脑 GABA 电路的改变可促进可卡因的自我管理

• 批准号: 10405526
• 负责人: John A. Dani
• 金额: $ 53.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405526
• 关键词: Abstinence; Animal Model; Attenuated; Behavior; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chlorides; Cocaine; Cocaine Abuse; Cocaine use disorder; Consumption; Data; Dependence; Dopamine; Dose; Down-Regulation; Drug Administration Routes; Extinction (Psychology); FDA approved; Goals; Hospitalization; Human; Infusion procedures; Maintenance; Measures; Membrane; Midbrain structure; Modeling; Molecular; Molecular Target; Neuraxis; Neurons; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Physiological; Protocols documentation; Public Health; Relapse; Research; Rodent Model; Self Administration; Testing; Therapeutic; Time; United States National Center for Health Statistics; Volition; addiction; base; cell type; chloride-cotransporter potassium; cocaine exposure; cocaine relapse; cocaine relapse prevention; cocaine self-administration; cocaine use; experimental study; gamma-Aminobutyric Acid; neuroadaptation; new therapeutic target; novel; prevent; promoter; side effect; stimulant abuse; therapeutic target

Project Summary. Cocaine is the most widely abused psychostimulant by a wide margin, and it remains a major public health problem in the US. Cocaine use was slowly declining, but in recent years there has been a resurgence in cocaine abuse accompanied by a sharp increase in cocaine-related hospitalizations and deaths. These facts highlight the need for effective medications for cocaine use disorder (CUD) because there are presently no FDA- approved pharmacologic treatments for CUD. Our exciting preliminary results highlight a novel molecular substrate that could be targeted to attenuate or prevent cocaine taking and seeking. Specifically, we show that cocaine exposure alters the expression of KCC2, a K+-Cl- cotransporter that defines the Cl- gradient in midbrain GABA neurons. Importantly, this cocaine-induced neuroadaptation is associated with circuitry changes in midbrain GABA neurons that promote and elevate further cocaine taking. These findings support the working hypothesis that initial cocaine taking alters midbrain GABAergic circuitry and increases the vulnerability for increased cocaine consumption over time. Thus, KCC2 represents a potential therapeutic target to treat CUD. KCC2 is expressed primarily in the central nervous system, and it is amenable to therapeutic manipulation in humans. KCC2 is highly attractive as a therapeutic target because it is usually constitutively highly active. Therefore, when normal subjects are treated with KCC2 activators, KCC2 activity is already high, such that attempts to increase its activity further do not produce deleterious side effects. Under normal physiological conditions, KCC2 maintains a low intra-neuronal Cl- concentration required for hyperpolarizing, inhibitory GABAergic currents. Our preliminary results indicate that cocaine dose-dependently downregulates KCC2 function in midbrain GABA neurons, thereby altering midbrain GABAergic circuitry. As a consequence of these circuitry changes, downregulation of KCC2 leads to increased cocaine self-administration. That is, cocaine use itself, by downregulating KCC2, perpetuates heavy cocaine self-administration. Our preliminary results indicate that if we prevent KCC2 downregulation or correct KCC2 function, then we decrease cocaine self-administration. The overall goal of this proposal is to characterize the functional state of the midbrain GABAergic circuitry and the disposition of KCC2 function during cocaine self-administration, extinction, and the reinstatement of cocaine seeking (Aims1 & 2). At each phase of the addiction cycle, we will determine the functional state of the midbrain GABAergic circuitry as a causal contributor to cocaine taking or seeking. Finally, we will apply two mechanistically different pharmacotherapies to boost KCC2 function to decrease cocaine self-administration and cocaine-seeking behavior during abstinence (Aim3). These translationally-relevant studies will test potential therapeutic drugs acting to boost KCC2 function to mitigate enhanced cocaine self-administration induced by cocaine itself. The proposed studies of KCC2 as a novel therapeutic target to mitigate CUD are timely, highly significant, and appropriately aimed at the factors underlying the transition to heavy cocaine use.

项目摘要。 可卡因是最广泛滥用的精神刺激剂，它仍然是主要的公众 美国的健康问题。可卡因的使用缓慢下降，但近年来，人们一直在复兴 可卡因滥用伴随着与可卡因有关的住院和死亡的急剧增加。这些事实 强调需要有效的可卡因使用障碍药物（CUD），因为目前没有FDA- 批准的CUD药理治疗。我们令人兴奋的初步结果突出了一种新颖的分子 可以针对可卡因和寻求可卡因的底物。具体来说，我们表明 可卡因暴露改变了KCC2的表达，KCC2是一种K+-Cl-共转运蛋白，该表达定义了中脑中的Cl-梯度 GABA神经元。重要的是，这种可卡因诱导的神经适应与电路变化有关 促进和提升更多可卡因的中脑GABA神经元。这些发现支持工作 假设最初可卡因服用中脑gabaergic电路，并增加了脆弱性 随着时间的流逝，可卡因消费量增加。因此，KCC2代表了治疗CUD的潜在治疗靶标。 KCC2主要在中枢神经系统中表达，并且可以进行治疗操作 在人类中。 KCC2作为治疗靶标具有很高的吸引力，因为它通常具有组成型高度活跃。 因此，当正常受试者用KCC2激活剂处理时，KCC2活性已经很高，这样 尝试进一步增加活动的尝试不会产生有害的副作用。在正常生理下 条件，KCC2维持低极化，抑制性所需的低神经内CL浓度 GABA能电流。我们的初步结果表明可卡因剂量依赖性地下调KCC2功能 在中脑GABA神经元中，从而改变了中脑GABA能电路。由于这些电路的结果 变化，KCC2的下调导致可卡因自我管理增加。也就是说，可卡因自身使用 下调KCC2，使大量可卡因自我管理永久化。我们的初步结果表明，如果我们 防止KCC2下调或纠正KCC2功能，然后我们减少可卡因自我管理。 该提案的总体目标是表征中脑Gabaergic电路的功能状态 可卡因自我给药，灭绝和恢复原状的KCC2功能的处理 可卡因寻求（AIMS1和2）。在成瘾周期的每个阶段，我们将确定 中脑GABA能回路是可卡因服用或寻求可卡因的因果关系。最后，我们将申请两个 机械上不同的药物疗法以提高KCC2功能以降低可卡因自我给药和 禁欲期间可卡因的行为（AIM3）。这些与翻译有关的研究将测试潜力 作用着提高KCC2功能的治疗药物可减轻可卡因的增强自我给药。 可卡因本身。提议的KCC2作为缓解CUD的新型治疗靶标的拟议研究非常及时，高度 重要的，并且适当地针对向大量可卡因过渡的基本因素。