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

据估计，成瘾每年给美国经济造成近5000亿美元的损失。这个 驱动这种行为的机制尚不清楚，但涉及药物条件线索。在动物模型中，这是 归因于前额叶皮质(PFC)中多巴胺和谷氨酸神经元之间的相互作用。 然而，对这种相互作用背后的细胞机制仍然缺乏了解。这 妨碍制定有效的成瘾药物治疗策略。长期的 这项建议的目的是识别PFC中可能提供有效治疗的细胞异常 目标是恢复功能，从而防止再次吸毒。在锥体神经元中，放电模式 在药物自我给药过程中，β-肾上腺素能受体(β-R)的多巴胺激活在一定程度上是调节的。 AR)，增加细胞内钙离子。这将激活KCNQ通道以控制尖峰频率 适应性，这限制了动作电位激发的频率。这项提议的中心假设是 慢性可卡因自身给药可上调β-AR信号转导通路，抑制KCNQ- 线索诱导的可卡因找寻恢复过程中的中介抑制。探索两国之间的相互作用 多巴胺和KCNQ对PFC神经元的抑制作用，我们将记录由KCNQ介导的耦合电流 致β-Ars.膜片钳记录将在大鼠的急性脑片上进行，这些大鼠接受了自我训练 在线索诱导的恢复之前或之后，给予可卡因和对照组(带轭的生理盐水)大鼠。这个 多巴胺抑制的KCNQ信号对修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进行审查。当激活初级PFC(PL)时 下丘脑室旁核(PFC，IL)的投射抑制可卡因的寻找。因此，AIM-2 将研究多巴胺抑制的KCNQ信号是否是PL特有的，或者也出现在IL中。 AIM-3将评估在复发期间操纵β-AR信号是否使KCNQ适应正常化。这个 拟议中的实验结果预计将对人类健康产生积极影响，因为它们应该 确定新的细胞靶点，用于开发治疗药物寻求行为的改进疗法。

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 (β- 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 β-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 β-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 β-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.