Dysregulation of midbrain GABAergic circuitry contributes to the motivational properties of cocaine

中脑 GABA 能回路的失调导致可卡因的动机特性

• 批准号: 10398981
• 负责人: Alexey Ostroumov
• 金额: $ 15.93万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398981
• 关键词: Acute; Addictive Behavior; American; Animal Model; Animals; Anions; Area; Attenuated; Behavior; Brain; Brain region; Cessation of life; Characteristics; Chlorides; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine use disorder; Data; Development; Down-Regulation; Drug Targeting; Drug Use Disorder; Functional disorder; Future; Goals; Health; Human; Impairment; In Vitro; Intake; Label; Lateral; Learning; Measures; Medial; Mediating; Mentorship; Methods; Midbrain structure; Modeling; Molecular; Motivation; Neurons; Nucleus Accumbens; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiology; Play; Population; Property; Public Health; Publishing; Rattus; Receptor Activation; Reporting; Research; Rewards; Rodent; Role; Self Administration; Signal Transduction; Slice; Substance Use Disorder; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic; Time; Training; Transgenic Organisms; Ventral Tegmental Area; Viral; Volition; Work; addiction; cell type; cellular targeting; cocaine exposure; cocaine overdose; cocaine self-administration; cocaine use; cost; designer receptors exclusively activated by designer drugs; dopaminergic neuron; effective therapy; experimental study; gamma-Aminobutyric Acid; mesolimbic system; neural circuit; neural repair; neuroadaptation; neuropsychiatric disorder; novel; overdose death; receptor; reward circuitry; substance use; synaptic inhibition; therapeutic target; tool; translational model

Cocaine addiction remains a major public health problem in the US, but effective treatments are still lacking. Cocaine use disorder is characterized by the development of pathological motivation for cocaine, characterized by intake in the face of rising costs and harmful consequences. Decreasing excessive motivational importance of drug taking without altering motivation for natural rewards is among the major goals of treating cocaine addiction. However, development of new pharmacotherapies requires understanding the basic brain mechanisms underlying cocaine addiction. Identifying these mechanisms is timely because cocaine use and overdoses have been increasing over the last several years. A growing body of evidence indicates that midbrain circuits play a critical role in cocaine-related behaviors. My preliminary data in rodents indicate that cocaine, but not sucrose, dysregulates midbrain inhibitory circuitry via decreased function of anion transporter, KCC2, located in VTA GABA neurons. This form of cocaine-induced neuroadaptation in GABAergic signaling has not been described previously, and I plan to investigate its impact on cocaine self-administration in rats. Given my preliminary findings suggesting that KCC2 dysfunction contributes to motivational properties of cocaine, I will measure motivation for cocaine self- administration while manipulating KCC2 activity in the VTA. At the cellular level, KCC2 dysfunction attenuates GABAA receptor-mediated inhibition leading to hyperexcitability of VTA GABA neurons. To assess the role of VTA GABA neurons in cocaine motivation, I will use chemogenetic approach in transgenic rat model to directly manipulate neuronal activity during cocaine self-administration. Ultimately, I will test if cocaine dysregulates GABAergic signaling in a circuit-specific manner. Accumulated evidence indicates that VTA GABA neurons project to multiple brain areas and I will focus on GABAergic projection to the nucleus accumbens, a brain region critically involved in motivational properties of addictive drugs. I will label specific VTA GABA projections to the medial and lateral shell of the nucleus accumbens and test the effect of cocaine on GABAergic signaling in these projections. Taken together, the research will illuminate the role of midbrain GABAergic circuitry in the pathological motivation for cocaine.

可卡因成瘾仍然是美国的一个主要公共卫生问题，但有效的治疗方法仍然存在 缺乏。可卡因使用障碍的特征是可卡因病理动机的发展， 其特点是在面临成本上升和有害后果的情况下采取措施。减少过多 主要目标之一是在不改变自然奖励动机的情况下吸毒的动机重要性 治疗可卡因成瘾。然而，新药物疗法的开发需要了解 可卡因成瘾的基本大脑机制。识别这些机制是及时的，因为可卡因 过去几年中，使用和过量用药一直在增加。 越来越多的证据表明，中脑回路在可卡因相关事件中发挥着关键作用 行为。我在啮齿类动物中的初步数据表明，可卡因（而非蔗糖）会导致中脑失调 通过位于 VTA GABA 神经元中的阴离子转运蛋白 KCC2 功能下降来抑制电路。这个表格 以前从未描述过可卡因诱导的 GABA 信号传导神经适应，我计划 研究其对大鼠可卡因自我给药的影响。鉴于我的初步调查结果表明 KCC2 功能障碍有助于可卡因的动机特性，我将测量可卡因自我的动机 给药同时操纵 VTA 中的 KCC2 活性。在细胞水平上，KCC2 功能障碍减弱 GABAA 受体介导的抑制导致 VTA GABA 神经元过度兴奋。评估的作用 VTA GABA 神经元在可卡因动机中的作用，我将在转基因大鼠模型中使用化学遗传学方法直接 在可卡因自我给药过程中操纵神经元活动。最终，我将测试可卡因是否失调 GABAergic 以电路特定方式发出信号。积累的证据表明 VTA GABA 神经元 投射到多个大脑区域，我将重点关注 GABA 能投射到伏隔核（大脑） 该区域与成瘾药物的动机特性密切相关。我将标记特定的 VTA GABA 投影 伏隔核的内侧和外侧壳并测试可卡因对 GABA 信号传导的影响 在这些预测中。总而言之，这项研究将阐明中脑 GABAergic 电路在 可卡因的病理动机。