Mechanisms of rostrocaudal differences in accumbal kappa opioid receptor effects on ethanol drinking

项目总结 在酒精使用障碍(AUD)中，酒精消费在一定程度上是由负面强化驱动的：消除 消极的情感状态。这种负强化在一定程度上是由强啡肽/kappa阿片类药物控制的。 受体(KOR)系统，涉及单胺、5-羟色胺(5-HT)和多巴胺(DA)。跨多个 在大脑区域，Kors的激活被发现会引起一种厌恶状态，这对 伏隔核(NAC)壳，位于尾侧亚区。然而，矛盾的是，KOR在嘴部的激活 南汽壳牌已被发现是有回报的。我们的初步数据，使用酒精饮用模型反映了 向依赖的转变表明，在吻侧NAC壳中的KOR激活促进了接近行为和 减少饮酒，而尾壳中的激活反而促进回避行为和酒精 喝酒。此外，虽然DA和5-羟色胺传入终止于吻壳和尾壳，但Kors有很远的 对尾壳DA释放有较大的抑制作用。我们假设嘴部的Kors被激活 NAC壳通过优先调节5-羟色胺与多巴胺，引起享乐性状态并抑制饮酒。 相比之下，尾侧NAC壳中KOR的激活会导致焦虑不安的状态，并通过以下方式增加酒精饮用量 优先调制DA而不是5-羟色胺。目的1研究KOR在脑内激活的具体假设。 鸡冠壳减少饮酒并产生积极情绪，KOR控制的平衡 单胺释放倾向于5-羟色胺。为了实现这一点，拟议中的实验，在NAC的吻端， 将使用药理学来确定KOR激活对(1)饮酒和(2)接近/回避的影响 行为学，分子生物学，(3)检测Kors在DA和5-HT终末的分布，以及 用电化学技术测量KOR激活对光刺激(4)DA和(5)5-羟色胺的影响。 目的2研究尾壳中KOR激活增强酒精饮酒的特殊假说 负性情绪，其中KORS对DA的影响最大。为了实现这一点，拟议中的实验， 在尾侧NAC壳中，将决定KOR激活对(1)饮酒和(2)的影响 接近/回避行为，(3)观察KRs在DA和5-HT终末的分布，并测量 KOR激活对视刺激(4)DA和(5)5-羟色胺的影响目标3阐明了驱动机制 这些对行为的矛盾影响。它研究了KOR介导的5-羟色胺抑制的具体假设。 NAC壳中的羟色胺活性抑制乙醇的消耗，而抑制DA活性则相反，并且 5-羟色胺和多巴胺的这些抑制作用分别在吻壳和尾壳中最为明显。因此， 拟议的实验将检测病毒KOR选择性表达对(1)DA和(2)的行为影响。 5-羟色胺在头壳和尾壳的终末，以及(3)DA和(4)5-羟色胺投射的化学发生抑制 这些次区域。了解KOR系统的不同功能最终可以促进设计 途径特异性疗法的出现，为AUD的治疗带来了革命性的变化。

PROJECT SUMMARY In alcohol use disorder (AUD), alcohol consumption is driven, in part, by negative reinforcement: the removal of the negative affective state. This negative reinforcement is governed, in part, by the dynorphin/kappa opioid receptor (KOR) system and involves the monoamines, serotonin (5-HT) and dopamine (DA). Across multiple brain regions, activation of KORs has been found to elicit a state of aversion, and this is also the case for the nucleus accumbens (NAc) shell, in the caudal subregion. Paradoxically, however, KOR activation in the rostral NAc shell has been found to be rewarding. Our preliminary data, using a model of ethanol drinking that reflects the transition to dependence, show that KOR activation in the rostral NAc shell promotes approach behavior and attenuates ethanol drinking, while activation in the caudal shell instead promotes avoidance behavior and ethanol drinking. Moreover, while DA and 5-HT afferents terminate in both the rostral and caudal shell, KORs have far greater inhibitory effects on DA release in the caudal shell. We hypothesize that activation of KORs in the rostral NAc shell elicits a hedonic state and inhibits ethanol drinking, by preferentially modulating 5-HT vs. DA; in contrast, KOR activation in the caudal NAc shell drives a dysphoric state and increases ethanol drinking, by preferentially modulating DA vs. 5-HT. Aim 1 investigates the specific hypothesis that KOR activation in the rostral shell reduces ethanol drinking and induces positive affect, with the balance of KOR control over monoamine release tipped towards 5-HT. To accomplish this, the proposed experiments, in the rostral NAc shell, will use pharmacology to determine effects of KOR activation on (1) ethanol drinking and (2) approach/avoidance behavior, molecular biology to (3) examine the distribution of KORs on DA and 5-HT terminals, and electrochemical techniques to measure effects of KOR activation on optically stimulated (4) DA and (5) 5-HT. Aim 2 investigates the specific hypothesis that KOR activation in the caudal shell potentiates ethanol drinking and negative affect, with KORs having their major effects on DA. To accomplish this, the proposed experiments, in the caudal NAc shell, will determine effects of KOR activation on (1) ethanol drinking and (2) approach/avoidance behavior, (3) examine the distribution of KORs on DA and 5-HT terminals, and measure effects of KOR activation on optically stimulated (4) DA and (5) 5-HT. Aim 3 clarifies the mechanism driving these paradoxical effects on behavior. It investigates the specific hypothesis that KOR-mediated inhibition of 5- HT activity in the NAc shell inhibits ethanol consumption, while inhibition of DA activity does the opposite, and that these effects of 5-HT and DA inhibition are most apparent in the rostral and caudal shell, respectively. Thus, the proposed experiments will examine behavioral effects of viral KOR expression selectively on (1) DA and (2) 5-HT terminals in the rostral and caudal shell, and chemogenetic inhibition of (3) DA and (4) 5-HT projections to these subregions. Understanding the diverse functions of the KOR system could ultimately facilitate the design of pathway-specific therapeutics, revolutionizing treatment for AUD.