Effects of repetitive cocaine administration in activity of cortical interneurons

描述（由申请人提供）：对可卡因等精神兴奋剂成瘾是一种严重的健康问题，涉及涉及认知和情感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理解由边缘回路介导的奖励过程，特别是可卡因的强化效应，这是由于突触前多巴胺转运体被阻断而导致多巴胺（DA）活性增加。然而，无法控制的药物寻找和减少自然奖励动机的细胞适应并没有得到很好的理解。最近对人类和动物的神经成像研究结果表明，大脑中还有其他区域，特别是前额叶皮层（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层活性低下：我们自己的细胞内体内记录表明，急性和反复服用可卡因都会破坏正常的膜在安静的下降状态和去极化的上升状态之间的过渡，在这种状态下会发生spike放电。研究表明，来自PFC中VTA和gaba能中间神经元的DA神经支配有助于调节PFC网络中的周期性兴奋，这可能最终成为认知的基础。因此，反复使用可卡因导致的多巴胺能传递的改变可能导致中间神经元和锥体细胞的异常放电模式，从而改变皮层中各种信息的整合。本提案概述了电生理实验，以研究反复施用可卡因在PFC中间神经元中诱导的持久神经适应。这项工作是重要的，因为反复可卡因治疗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。利用反复使用可卡因的大鼠PFC的锥体细胞和中间神经元进行体外全细胞钳记录和体内细胞内、细胞外记录。这一提议的首要假设是，反复服用可卡因会增加皮质GABA中间神经元的活动。叙述：可卡因等精神兴奋剂成瘾是一种严重的健康问题，涉及涉及认知和情感处理的边缘和皮质回路的神经生物学变化。这一建议将评估潜在的新的细胞靶点，以获得更直接的治疗方法，希望能够针对反复使用精神兴奋剂所干扰的认知和情绪过程。

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.