Effects of repetitive cocaine administration in activity of cortical interneurons

描述（由申请人提供）：可卡因等精神兴奋剂成瘾是一种严重的健康问题，涉及参与认知和情感处理的边缘系统和皮层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作用，这是由于突触前多巴胺转运蛋白的阻断而导致多巴胺（DA）活性增加。然而，细胞的适应性，难以管理的药物寻求和自然奖励的动机减少的基础还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解释这种所谓的额叶皮层活动减退的潜在机制：我们自己的体内细胞内记录表明，急性和重复给予可卡因都会破坏平静的下行状态和去极化的上行状态之间的正常膜转换，在此期间会发生尖峰放电。研究表明，来自腹侧被盖区的DA神经支配和PFC中的GABA能中间神经元有助于调节PFC网络中的反复兴奋，这可能最终成为认知的基础。因此，可卡因重复治疗引起的多巴胺能传递的改变可能会诱导中间神经元和锥体细胞的异常放电模式，从而改变皮层中多种信息的整合。该建议概述了电生理实验，研究持久的神经适应性诱导的PFC中间神经元重复管理的可卡因。这项工作是重要的，因为重复可卡因治疗对皮质中间神经元的影响和改变PFC中GABA能抑制的后果尚未研究。体外全细胞钳夹记录以及体内细胞内和细胞外记录将从已用可卡因重复处理的大鼠PFC中的锥体细胞和中间神经元进行。这个建议的首要假设是，重复可卡因管理产生增加皮层GABA interneurons.Narrative的活动：成瘾的精神兴奋剂，如可卡因是一个严重的健康问题，涉及边缘系统和皮层电路，从事认知和情感处理的神经生物学变化。该研究将评估潜在的新细胞靶点，以获得更有针对性的治疗方法，有望靶向因重复使用精神兴奋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.