Selective Restoration of KCNQ Channel Inhibition in the PFC to Inhibit Cue-Induc

（c） 据估计，成瘾每年给美国经济造成近5万亿美元的损失。的 驱动这种行为的机制尚不清楚，但涉及药物条件的线索。在动物模型中， 归因于前额叶皮层（PFC）中多巴胺和谷氨酸神经元之间的相互作用。 然而，仍然缺乏对这种相互作用的细胞机制的理解。这 阻碍了成瘾的有效药物治疗策略的发展。长期 本提案的目的是确定PFC中的细胞异常， 目标是恢复功能，从而防止重新吸毒。在锥体神经元中， 在药物自我给药期间，部分地通过β-肾上腺素能受体的多巴胺活化来调节（（3- AR），其增加细胞内钙。这将激活KCNQ通道以控制尖峰频率 适应，限制动作电位放电的频率。这一提议的核心假设是， p-AR信号级联通过慢性可卡因自我给药上调，并抑制KCNQ- 介导的抑制在线索诱导恢复可卡因寻求。为了探索 多巴胺和KCNQ抑制PFC神经元，我们将记录电流介导的KCNQ耦合 的P-AR。膜片钳记录将在接受自我训练的大鼠的急性脑切片中进行， 在线索诱导的恢复之前或之后，给予可卡因和对照（轭化盐水）大鼠。的 多巴胺抑制的KCNQ信号对恢复的机制和功能影响尚不清楚 并将在本提案的前两个具体目标中加以审查。当前边缘PFC（PL）激活时， 启动可卡因寻求，来自边缘下PFC（IL）的投射抑制可卡因寻求。Aim-2 将检查多巴胺抑制的KCNQ信号传导是否特异于PL，或者也发生在IL中。 目的-3将评估P-AR信号传导的操纵是否使复发期间的KCNQ适应正常化。的 预期拟议实验的结果将对人类健康产生积极影响，因为它们应该 识别新的细胞靶点，用于开发治疗药物寻求行为的改进疗法。 相关性（见附件）： 药物滥用每年花费美国近5万亿美元（NIDA）， 治疗可以帮助降低这些费用。目前尚无有效的药物干预措施 可卡因成瘾KCNQ介导的谷氨酸传递神经适应的鉴定 可卡因自我给药后的皮质神经元有望揭示治疗的新细胞靶点。 发展，从而更好地理解。和治疗，放松对药物的需求。

instrucfions): Estimates indicate that addiction cost the U.S. economy neariy one half-trillion dollars per year. The mechanisms driving this behavior are unclear, but involve drug-conditioned cues. In animal models this is attributed to an interaction between dopamine and glutamate neurons In the prefrontal cortex (PFC). However, there remains a lack of understanding ofthe cellular mechanism underiying this interaction. This hampers the development of effective pharmacological treatment strategies for addiction. The long-term objective of this proposal is to identify cellular abnormalities in the PFC that may provide effective therapeutic targets to restore function and thereby prevent relapse to drug seeking. In pyramidal neurons, firing patterns during drug self-administration are regulated in part by dopamine activation of beta-adrenergic receptors ((3- AR), which increase intracellular calcium. This activates KCNQ channels to control spike frequency adaptation, which limits the frequency of action potential firing. The central hypothesis of this proposal Is that the p-AR -signaling cascade is upregulated by chronic cocaine self-administration and depresses KCNQ- mediated inhibition during cue-induced reinstatement of cocaine seeking. To explore the interaction between dopamine and KCNQ-inhibition in PFC neurons, we will record currents mediated by KCNQ that are coupled to of P-ARs. Patch-clamp recordings will be performed in acute brain slices from rats trained to self- administer cocaine and control (yoked saline) rats, before or after cue-induced reinstatement. The mechanism and functional impact ofthe dopamine-suppressed KCNQ signal on reinstatement is unknown and will be examined in the first two specific aims of this proposal. While activation ofthe prelimbic PFC (PL) initiates cocaine seeking, the projection from the infralimbic PFC (IL) inhibits cocaine seeking. Thus, Aim-2 will examine whether dopamine-suppressed KCNQ signaling is specific to the PL, or also occurs in the IL. Aim-3 will evaluate if manipulation of P-AR signaling normalizes the KCNQ adaptation during relapse. The results of the proposed experiments are expected to positively influence human health because they should identify novel cellular targets for development of improved therapies to treat drug-seeking behaviors. RELEVANCE (See instrucfions): Substance abuse costs the U.S. neariy one half-trillion dollars annually (NIDA), and pharmacological treatment can help reduce these costs. At present, there are no effective pharmacotherapeutic interventions for cocaine addiction. Identification ofthe KCNQ-mediated neuroadaptations in glutamate transmission in cortical neurons after cocaine self-administration is expected to reveal novel cellular targets for therapeutic development and therebv lead to a better understanding of. and treatment for, relaose to drug seeking.