Incentive Motivation in Addiction: PKA Mechanisms

描述（由申请人提供）：药物滥用和依赖定义了行为状态，包括以牺牲更适当的行为模式为代价增加对药物寻求和服用的行为分配。因此，成瘾可以被看作是期望药物对行为的增强控制（由于其无条件的、有益的特性）。同样清楚的是，与药物相关的（条件）刺激获得了更高的控制行为的能力。这些现象与腹侧纹状体和杏仁核内的多巴胺（DA）功能有关，并已具体描述为激励动机过程。我们的数据显示，持续的药物诱导的激励动机增强与边缘纹状体DA/cAMP/PKA/CREB活性的增加有关，并且可以被模仿，这表明DA调节的细胞内信号分子的适应可能是这些行为变化的基础。本研究将通过巴甫洛夫-工具转移（PIT）和条件强化（CR）范式的响应，确定杏仁核内的PKA/CREB信号如何促进激励动机过程的关联方面。该项目将重点关注这样一种假设，即由于杏仁核中PKA/CREB信号通路的改变，反复接触可卡因将导致激励动机过程的持续增强。具体来说，我们将研究以下假设。(1)反复可卡因暴露增强了激励动机，导致杏仁核PKA/CREB FosB功能的改变。将对先前暴露于可卡因的大鼠在（PIT）或（CR）食物配对条件刺激下的反应进行行为和分子改变检查。(2)未用药动物PKA/CREB信号的激活会增强激励动机。这将通过将PKA的直接激活剂/抑制剂和过度表达CREB或突变CREB的病毒载体注入杏仁核的基底外侧或中央核来检查。(3) PKA/CREB信号的抑制将阻断可卡因处理动物的增强激励动机。在CRE-LacZ转基因小鼠中，行为与CREB活性之间的相关性也将被研究。这些研究将共同确定可卡因诱导的杏仁核中PKA/CREB信号通路的激活是否会导致激励动机的增强，以及这些影响是否可以通过分别刺激或抑制PKA/CREB信号的操作来模拟或阻断。这些数据可能对理解动机过程的神经生物学及其对药物寻求行为的假定影响至关重要。可卡因在边缘纹状体区域产生的PKA/CREB信号的持续改变被假设有助于成瘾中的强迫性奖励寻求。

DESCRIPTION (provided by applicant): Drug abuse and dependence define behavioral states involving increased allocation of behavior towards drug seeking and taking at the expense of more appropriate behavioral patterns. As such, addiction can be viewed as increased control of behavior by the desired drug (due to its unconditioned, rewarding properties). It is also clear that drug-associated (conditioned) stimuli acquire heightened abilities to control behavior. These phenomena have been linked with dopamine (DA) function within the ventral striatum and amygdala and have been described specifically in terms of incentive motivational processes. Our data show that persistent drug-induced enhancement in incentive motivation are associated with, and can be mimicked by, increases in limbic-striatal DA/cAMP/PKA/CREB activity, suggesting that adaptations in DA-regulated intracellular signaling molecules may underlie these behavioral changes. The current proposal will determine how PKA/CREB signaling within the amygdala contributes to associative aspects of incentive motivational processes by using Pavlovian-to-lnstrumental Transfer (PIT) and responding for Conditioned Reinforcement (CR) paradigms. This project will focus on the hypothesis that repeated cocaine exposure will result in persistent enhancements in incentive motivational processes due to alterations in the PKA/CREB signaling pathway in the amygdala. Specifically, we will investigate the following hypotheses. (1) Repeated cocaine exposure enhances incentive motivation and results in alterations of PKA/CREB FosB function in the amygdala. Behavioral and molecular alterations will be examined in rats previously-exposed to cocaine either responding in the presence of (PIT) or for (CR) food-paired conditioned stimuli. (2) Activation of PKA/CREB signaling in drug naive animals will augment incentive motivation. This will be examined using infusions of direct activators/inhibitors of PKA and viral vectors that over-express CREB or mutant CREB into the basolateral or central nucleus of the amygdala. (3) Inhibition of PKA/CREB signaling will block augmented incentive motivation in cocaine-treated animals. Correlations between behavior and CREB activity will also be examined in CRE-LacZ transgenic mice. Together these studies will determine whether cocaine-induced activation of the PKA/CREB signaling pathway in the amygdala results in augmented incentive motivation and whether these effects can be mimicked or blocked by manipulations that stimulate or inhibit PKA/CREB signaling, respectively. These data may be critical for understanding the neurobiology of motivational processes and their putative impact on drug-seeking behavior. Persistent alterations in PKA/CREB signaling in limbic-striatal regions produced by cocaine are hypothesized to contribute to compulsive reward seeking in addiction.