Effects of repeated cocaine administration in activity of cortical interneurons.

对可卡因等精神刺激剂的上瘾是一个涉及神经生物学的严重健康问题 参与认知和情绪处理的边缘和大脑皮层回路的变化。直到最近，大多数 研究的重点是了解边缘环路介导的奖赏过程，特别是 可卡因的增强效应，其原因是由于阻断 突触前多巴胺转运体。然而，细胞适应的基础上难以管理的药物寻求和 对自然奖赏动机的降低还不能很好地理解。 对人类和动物的影响涉及到额外的大脑区域，特别是前额叶皮质(RFC)。 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，急性和重复的 服用可卡因扰乱了正常的细胞膜在安静的“低谷状态”和 去极化的“向上状态”，在此期间发生尖峰放电。已有研究表明，多巴胺的神经支配来自 RFC中的VTA和GABA能中间神经元有助于调节RFC网络中的经常性兴奋，这可能 归根结底，认知是基础。反复用药引起的多巴胺能传递的改变 因此，可卡因可以诱导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 研究重复给予可卡因对RFC中间神经元耐受性神经适应的影响。 这项工作意义重大，因为反复处理可卡因对皮层中间神经元和 改变RFC中GABA能抑制的后果还没有研究。全细胞钳位 体外记录和活体细胞内和细胞外记录将由锥体细胞和 反复使用可卡因的大鼠RFC内的中间神经元。最重要的假设 这一建议的结论是，反复服用可卡因会增加皮质GABA的活性 中间神经元。

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 (RFC). 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 disrupt 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 RFC help tune the recurrent excitation in RFC 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 RFC 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 RFC 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 RFC 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.