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

可卡因成瘾在美国仍然是一个主要的公共健康问题，但有效的治疗方法仍然 缺乏。可卡因使用障碍的特征是可卡因的病理动机的发展， 其特点是在面对不断上升的成本和有害后果的情况下摄入。减少过度 在不改变对自然回报的动机的情况下吸毒的动机重要性是主要目标之一 治疗可卡因成瘾。然而，开发新的药物疗法需要了解 可卡因成瘾的基本大脑机制。确定这些机制是及时的，因为可卡因 在过去的几年里，使用和过量的药物一直在增加。 越来越多的证据表明，中脑回路在与可卡因相关的过程中起着关键作用 行为。我在啮齿动物身上的初步数据表明，可卡因，而不是蔗糖，会扰乱中脑 位于VTA-GABA神经元中的负离子转运体KCC2功能减弱，从而抑制通路。此表格 可卡因诱导的神经适应在GABA能信号中的作用以前没有描述过，我计划 研究其对大鼠可卡因自身给药的影响。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，我将测量可卡因的动机自我 在VTA中操作KCC2活动的同时进行管理。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神经元的过度兴奋。评估……的作用 VTA-GABA神经元在可卡因动机中的作用，我将利用化学遗传学的方法在转基因大鼠模型中直接 在可卡因自我给药过程中操纵神经元活动。最终，我会测试可卡因是否会失调 以特定于电路的方式发出GABA能信号。越来越多的证据表明，VTA GABA神经元 投射到多个大脑区域，我将专注于GABA能投射到伏隔核，一个大脑 与成瘾药物的激励特性密切相关的地区。我会标明具体的VTA GABA预测 伏核内侧壳核和伏隔核外侧壳核测可卡因对GABA能信号的影响 在这些预测中。综上所述，这项研究将阐明中脑GABA能回路在 可卡因的病理性动机。

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.