Incentive Motivation and Addiction: PKA Mechanisms

描述（由申请人提供）：药物相关线索引起成瘾者的渴望和复发，并有助于成瘾的进展和持续。本研究的目的是建立新的行为和药理学方法，通过降低药物线索的动机意义来有效和持续地减少复发，并阐明相应的神经生物学机制。我们已经确定了药物诱导的杏仁核DA/ camp调节信号的改变，这种改变促进了与奖励相关的学习和记忆过程，导致了更强的与奖励相关的记忆，并通过作为条件强化物的线索加强了行为控制。虽然我们关注的是DA/cAMP调节的信号级联，但最近的生化和药理学研究表明，cAMP激活至少两个不同的细胞内信号靶点：蛋白激酶A （PKA）和cAMP激活的交换蛋白（Epac）。Epac在杏仁核基底外侧核（BLA）和前额叶皮质（PFC）中高度表达，但其在大脑中的作用几乎未知。我们的新数据证实了PKA和Epac对BLA和pfc依赖性行为的调节。在这里，我们将验证一个假设，即中断的线索药物记忆的重新巩固和增强的消失巩固都可以减少线索诱导的复发。为了了解camp调控的细胞事件在这些过程中的作用，我们将在非强化提示暴露后选择性激活或抑制PKA和Epac，以独立改变再巩固或消失机制。随后的测试将检查线索诱导的恢复和可卡因相关线索作为条件强化物的能力。目的1将使用杏仁核操作来破坏记忆再巩固，以减少线索药物关联的强度。我们的数据表明，在可卡因配对线索重新激活后，杏仁核中注入cAMP信号抑制剂可以减少线索诱导的恢复和条件强化反应，这与有关可卡因寻求行为可以通过破坏线索药物记忆来减少的报道一致。目的2将使用PFC操作（边缘下和边缘前）来增强可卡因相关线索的消失。这些研究还将调查选定的操作对新获得的或旧的线索记忆的影响和持久性，以及表征cAMP/PKA/Epac活性的变化。目标3将使用目标1和目标2中确定的干预措施，以发现破坏再整合和增强灭绝整合的方法组合是否可以产生更深远的影响。线索诱导的恢复和条件强化的减少以及线索消失的上下文依赖性的改变将被检查。我们还将确定可卡因引起的cAMP/PKA/Epac活性的改变是否会通过使线索药物记忆重新巩固而不是在重新激活时消失，从而诱发持久的、适应性不良的药物相关记忆。总之，这些研究应该确定线索诱导的渴望和复发的过程，以便开发新的行为和药物治疗策略。这项研究的目的是了解camp调节的信号过程如何通过改变记忆的再巩固和消失来减少对可卡因记忆的行为控制，而记忆的再巩固和消失分别依赖于杏仁核和前额叶皮层的亚区。我们还将验证这样一个假设，即可卡因在这些区域引起的神经适应可能会使线索记忆更容易经历重新巩固，而不是消失，从而促进与药物相关的不适应记忆的发展和持续，以及它们沉淀可卡因寻找和服用行为的能力。了解这些机制可以用来确定新的行为和药物治疗策略，以有效和持续地降低可卡因相关线索诱导复发的能力，从而对抗成瘾。

DESCRIPTION (provided by applicant): Drug-associated cues elicit craving and relapse in addicts and contribute to the progression and persistence of addiction. The objective of this research is to establish novel behavioral and pharmacological methods to effectively and persistently reduce relapse by decreasing the motivational significance of drug cues, and to elucidate the corresponding neurobiological mechanisms. We have identified drug-induced alterations in amygdala DA/cAMP-regulated signaling that promote reward-related learning and memory processes, result in stronger reward-associated memories, and that enhance behavioral control by cues acting as conditioned reinforcers. While we have focused on DA/cAMP-regulated signaling cascades, recent biochemical and pharmacological studies show that cAMP activates at least two distinct intracellular signaling targets: protein kinase A (PKA) and exchange protein activated by cAMP (Epac). Epac is highly expressed in the basolateral nucleus of the amygdala (BLA) and prefrontal cortex (PFC) but its role in brain is virtually unknown. Our new data confirm regulation of BLA- and PFC-dependent behaviors by both PKA and Epac. Here, we will test the hypothesis that both disrupted reconsolidation of cue-drug memories and enhanced consolidation of extinction can reduce cue-induced relapse. To understand the role of cAMP-regulated cellular events in these processes we will use selective activation or inhibition of PKA and Epac given after non-reinforced cue exposures to independently alter reconsolidation or extinction mechanisms. Subsequent tests will examine cue-induced reinstatement and the ability of cocaine-associated cues to act as conditioned reinforcers. Aim 1 will use amygdalar manipulations to disrupt memory reconsolidation to reduce the strength of cue-drug associations. Our data demonstrate that amygdala infusions of inhibitors of cAMP signaling after reactivation of a cocaine- paired cue can reduce both cue-induced reinstatement and responding with conditioned reinforcement, consistent with reports that cocaine-seeking behavior can be reduced by disruption of cue-drug memories. Aim 2 will use PFC manipulations (infralimbic vs. prelimbic) to enhance extinction of cocaine-associated cues. These studies will also investigate the impact and persistence of selected manipulations on newly acquired or older cue memories as well as characterize resulting alterations in cAMP/PKA/Epac activity. Aim 3 will use interventions identified in Aims 1 & 2 to discover if a combination of approaches that disrupt reconsolidation and enhance consolidation of extinction together can have more profound effects. Reductions in cue-induced reinstatement and conditioned reinforcement as well as altered context dependency of cue extinction will be examined. We will also determine if cocaine-induced alterations in cAMP/PKA/Epac activity induce persistent, maladaptive, drug-associated memories by biasing cue-drug memories to undergo reconsolidation, as opposed to extinction when reactivated. Together these studies should identify processes that underlie cue- induced craving and relapse in order to develop novel behavioral and pharmacological treatment strategies. The goal of the proposed research is to understand how cAMP-regulated signaling processes can be used to reduce the behavioral control of cue-cocaine memories through alterations in memory reconsolidation and extinction - opposing mnemonic processes that depended on subregions of the amygdala and prefrontal cortex, respectively. We will also test the hypothesis that cocaine-induced neuroadaptations in these regions may predispose cue memories to undergo reconsolidation, as opposed to extinction, and thereby contribute to the development and persistence of maladaptive drug-associated memories and their ability to precipitate cocaine-seeking and -taking behavior. Understanding these mechanisms can be used to identify novel behavioral and pharmacological treatment strategies to effectively and persistently reduce the ability of cocaine-associated cues to induce relapse in order to combat addiction.