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，增加了对药物寻找和服用的行为分配。因此，上瘾可以被视为通过所需药物(由于其无条件的、有益的特性)加强对行为的控制。同样清楚的是，药物相关的(条件性)刺激获得了更强的控制行为的能力。这些现象与腹侧纹状体和杏仁核中的多巴胺(DA)功能有关，并已在激励动机过程方面进行了专门描述。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，并可以被其模仿，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。目前的建议将确定杏仁核内的PKA/CREB信号如何通过使用巴甫洛夫转移(PIT)和反应条件强化(CR)范式来促进激励动机过程的关联方面。这个项目将集中于这样的假设，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。具体地说，我们将研究以下假设。(1)反复暴露可卡因可增强刺激动机，并导致杏仁核PKA/CREB FosB功能改变。行为和分子的变化将在以前暴露于可卡因的大鼠身上进行检测，无论是在(PIT)或(CR)食物配对条件刺激下做出反应。(2)药物幼稚动物体内PKA/CREB信号的激活将增强激励动机。这将通过将PKA的直接激活物/抑制物和过度表达CREB或突变的CREB的病毒载体注入杏仁核的基底外侧核或中央核来检验。(3)抑制PKA/CREB信号通路将阻断可卡因刺激动物增强的刺激动机。Cre-LacZ转基因小鼠的行为和CREB活性之间的相关性也将得到检验。总之，这些研究将确定可卡因诱导的杏仁核PKA/CREB信号通路的激活是否会导致激励动机的增强，以及这些效应是否可以分别被刺激或抑制PKA/CREB信号的操作所模仿或阻断。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找行为的假定影响至关重要。由可卡因产生的边缘-纹状体区域PKA/CREB信号的持续变化被认为有助于成瘾时的强迫性奖赏寻求。

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.