Effects of repetitive cocaine administration in activity of cortical interneurons

描述(申请人提供)：对可卡因等精神刺激剂的上瘾是一个严重的健康问题，涉及参与认知和情绪处理的边缘和皮质回路的神经生物学变化。直到最近，大多数工作都集中在了解边缘环路介导的奖赏过程，特别是可卡因的增强效应，这是由于阻断突触前DA转运体而导致的多巴胺(DA)活性增加所致。然而，无法控制的药物寻求和自然奖励动机降低背后的细胞适应并没有被很好地理解。最近对人类和动物的神经成像研究结果表明，大脑中有更多的区域，特别是前额叶皮质(PFC)。最近的几项研究提出了可能的机制，可以解释这种所谓的额叶皮质活动不足：我们自己在体内的细胞内记录显示，急性和重复服用可卡因都扰乱了正常的膜转换，在平静的低态和去极化的高态之间，发生了尖峰放电。研究表明，来自PFC的VTA和GABA能中间神经元的DA神经支配有助于调节PFC网络中的经常性兴奋，这可能最终构成认知的基础。因此，重复使用可卡因引起的多巴胺能传递的改变可能会导致中间神经元和锥体细胞的异常放电模式，从而改变大脑皮层中不同信息的整合。这项建议概述了电生理学实验，以研究重复给予可卡因诱导的PFC中间神经元的持久神经适应。这项工作是有意义的，因为反复处理可卡因对皮质中间神经元的影响以及改变PFC中GABA能抑制的后果尚未被研究。体外的全细胞钳制记录和体内的细胞内和细胞外记录将来自反复用可卡因处理的大鼠PFC中的锥体细胞和中间神经元。这一建议的主要假设是，反复服用可卡因会增加皮质GABA神经元的活性。这篇论文将评估潜在的新细胞靶点，以寻求一种更有针对性的治疗方法，有望针对因反复使用精神刺激剂而受到干扰的认知和情感过程。

DESCRIPTION (provided by applicant): Addiction to psychostimulants such as cocaine is a serious health problem that involves neurobiological changes in limbic and cortical circuits that engage cognitive and emotive processing. Until recently, most work has focused on understanding the reward processes mediated by limbic circuits, particularly the reinforcing effects of cocaine that result from increased dopamine (DA) activity due to blockade of the presynaptic DA transporter. However, the cellular adaptations that underlie unmanageable drug seeking and reduced motivation for natural reward are not as well understood. Results from recent neuroimaging studies in humans and animals have implicated additional brain areas, particularly the prefrontal cortex (PFC). Several recent studies have suggested potential mechanisms that could account for such a purported hypoactive frontal cortex: Our own intracellular recordings in-vivo show that both acute and repeated administration of cocaine disrupts the normal membrane transitions between quiet down-states and depolarized up-states during which spike firing occurs. It has been shown that DA innervation from the VTA and GABAergic interneurons in the PFC help tune the recurrent excitation in PFC networks that may ultimately underlie cognition. Alterations in dopaminergic transmission resulting from repeated treatment with cocaine could therefore induce aberrant firing patterns in interneurons and pyramidal cells, thus altering the integration of diverse information in the cortex. This proposal outlines electrophysiological experiments to study the enduring neuroadaptations induced in PFC interneurons by repeated administration of cocaine. This work is significant because the effects of repeated cocaine treatment on cortical interneurons and the consequences of altering GABAergic inhibition in the PFC have not been studied. Whole-cell clamp recordings in vitro and intracellular and extracellular recordings in vivo will be made from pyramidal cells and interneurons in the PFC of rats that have been treated repeatedly with cocaine. The overarching hypothesis of this proposal is that repeated cocaine administration produces increases in the activity of cortical GABA interneurons.Narrative: Addiction to psychostimulants such as cocaine is a serious health problem that involves neurobiological changes in limbic and cortical circuits that engage cognitive and emotive processing. This porposal will evaluate potential new cellular targets for a more directed therapeutical approach that hopefully could target the cognitive and emotive processes disturbed by the repeated use of psychostimulants.