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: 10574548
• 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/10574548
• 关键词: Abstinence; Animal Model; Attenuated; Behavior; Centers for Disease Control and Prevention (U.S.); Central Nervous System; Cessation of life; Chlorides; Cocaine; Cocaine Abuse; Cocaine use disorder; Consumption; Data; Dependence; Dose; Down-Regulation; Drug Administration Routes; Extinction; FDA approved; Goals; Hospitalization; Human; Infusion procedures; Maintenance; Measures; Membrane; Midbrain structure; Modeling; Molecular; Molecular Target; Neurons; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Phosphorylation; Physiological; Proteins; Protocols documentation; Public Health; Relapse; Research; Rodent Model; Self Administration; Testing; Therapeutic; Time; United States National Center for Health Statistics; addiction; cell type; chloride-cotransporter potassium; cocaine exposure; cocaine relapse; cocaine relapse prevention; cocaine seeking; cocaine self-administration; cocaine use; dopaminergic neuron; drug action; experimental study; gamma-Aminobutyric Acid; neuroadaptation; new therapeutic target; novel; prevent; promoter; side effect; stimulant abuse; symporter; 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。 可卡因是滥用最广泛的精神兴奋剂，并且仍然是主要的公众药物 美国的健康问题。可卡因的使用缓慢下降，但近年来有所回升 可卡因滥用伴随着与可卡因相关的住院和死亡人数急剧增加。这些事实 强调需要针对可卡因使用障碍 (CUD) 的有效药物，因为目前 FDA 还没有 批准的 CUD 药物治疗。我们令人兴奋的初步结果突出了一种新型分子 可用于减少或防止可卡因吸食和寻找的底物。具体来说，我们表明 可卡因暴露会改变 KCC2 的表达，KCC2 是一种 K+-Cl- 协同转运蛋白，定义中脑中的 Cl- 梯度 GABA 神经元。重要的是，这种可卡因诱导的神经适应与神经回路的变化有关 中脑 GABA 神经元促进和提高进一步可卡因的摄入。这些发现支持了工作 假设最初服用可卡因会改变中脑 GABA 电路并增加对可卡因的脆弱性 随着时间的推移，可卡因的消费量增加。因此，KCC2 代表了治疗 CUD 的潜在治疗靶点。 KCC2 主要在中枢神经系统中表达，并且适合治疗操作 在人类中。 KCC2 作为治疗靶点非常有吸引力，因为它通常具有高度活性。 因此，当正常受试者接受KCC2激活剂治疗时，KCC2活性已经很高，使得 进一步增加其活性的尝试不会产生有害的副作用。正常生理情况下 条件下，KCC2 维持超极化、抑制所需的低神经元内 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 中脑 GABA 神经元，从而改变中脑 GABA 能电路。由于这些电路 变化时，KCC2 的下调会导致可卡因自我给药增加。也就是说，可卡因通过自身使用 下调 KCC2，使重度可卡因自我给药永久化。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给药。 该提案的总体目标是表征中脑 GABAergic 电路的功能状态 以及可卡因自我给药、灭绝和恢复过程中 KCC2 功能的处置 寻找可卡因（目标 1 和 2）。在成瘾周期的每个阶段，我们将确定成瘾周期的功能状态 中脑 GABA 能回路是吸食或寻找可卡因的因果因素。最后，我们将应用两个 机制上不同的药物疗法可增强 KCC2 功能，减少可卡因自我给药和 戒断期间寻求可卡因的行为（目标 3）。这些与转化相关的研究将测试潜力 治疗药物可增强 KCC2 功能，以减轻由可卡因引起的增强的可卡因自我给药 可卡因本身。 KCC2 作为减轻 CUD 的新治疗靶点的拟议研究是及时的、高度的 重要的，并适当针对向可卡因大量使用过渡的潜在因素。