Cognitive dysfunction after chronic PCP, THC and cocaine

描述（由申请人提供）：本提案的目的是定义反复药物暴露对成瘾认知缺陷的激励、动机过程和抑制控制改变的行为后果和细胞相关性。在人类和动物身上进行的神经行为研究开始确定药物引起的认知动机过程的改变，脑成像研究显示药物滥用者的皮质-边缘-纹状体活动发生了改变。我们在动物身上的研究表明，药物诱导的多巴胺（DA）神经传递和蛋白激酶A （PKA）信号的改变可能导致分子神经适应。先前资助期的研究首次表明，在猴子和大鼠中，反复暴露于PCP、可卡因或THC会产生与抑制控制相关的长期认知障碍，这是额叶皮质区域DA功能障碍的特征，并与之相关。这些认知障碍伴随着激励动机过程的改变和皮质下DA功能的增强。我们的新数据表明，这些持续的药物诱导的行为变化也与DA/PKA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动机过程改变的基础。药物诱导的突触DA增加刺激D1受体，从而增加cAMP水平，导致PKA激活。PKA激活增加了转录因子的表达和参与神经元兴奋性/可塑性的底物蛋白的磷酸化，如DA和camp调节的32 kDa磷酸化蛋白（DARPP-32）。目前的研究建议深入研究反复药物暴露如何持续改变认知/抑制功能，激励动机和DA/PKA信号。在目的1中，反复使用可卡因、PCP和THC对猴子和大鼠依赖于腹内侧vs背外侧额叶皮层的认知抑制功能的影响将被检查。在目标2中，我们将使用刺激-奖励学习和条件强化来研究药物暴露对激励动机的影响，并将这些研究扩展到猴子和可卡因自我管理大鼠。另一个目标是确定这些药物诱导的行为改变是否与皮质边缘纹状体区域中DA/ pka调节的信号通路的改变有关，并将假定的分子变化与行为联系起来。我们建议将重点放在DA/PKA调控蛋白DARPP-32上，因为它可以用于评估DA/PKA信号的抑制和扩增，并且它在皮质边缘和纹状体区域表达。目的3将直接验证这样的假设：通过局部输注PKA抑制剂/激活剂，皮质PKA活性的降低和边缘纹状体PKA活性的增强可以模拟先前药物暴露的影响，并检查药物诱导的缺陷是否可以通过输注PKA调节剂来逆转。

DESCRIPTION (provided by applicant): The objective of this proposal is to define behavioral consequences and cellular correlates of repeated drug exposure on alterations in incentive motivational processes and inhibitory control contributing to cognitive deficits in addiction. Neurobehavioral studies in humans and animals are beginning to define drug-induced alterations in cognitive-motivational processes, and brain imaging studies show altered cortico-limbic-striatal activity in drug abusers. Our studies in animals have contributed to the idea that drug-induced alterations in dopamine (DA) neurotransmission and protein kinase A (PKA) signaling may result in molecular neuroadaptations. Studies from the previous funding period are among the first to show that repeated exposure to PCP, cocaine or THC produces long-lasting cognitive impairments associated with inhibitory control in monkeys and rats, deficits characteristic of, and correlated with, DA dysfunction in regions of the frontal cortex. These cognitive impairments are concomitant with alterations in incentive motivational processes and enhanced subcortical DA function. Our new data show that these persistent drug-induced behavioral changes are also associated with, and can be mimicked by, increases in DA/PKA activity, suggesting that adaptations in DA-regulated intracellular signaling molecules may underlie alterations in motivational processes. Drug-induced increases in synaptic DA stimulate D1 receptors, which increase cAMP levels, leading to activation of PKA. PKA activation increases expression of transcription factors and phosphorylation of substrate proteins involved in neuronal excitability/plasticity such as the DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). The current research proposes an intensive examination of how repeated drug exposure persistently alters cognitive/inhibitory function, incentive motivation and DA/PKA signaling. In Aim 1, the effects of repeated cocaine, PCP, and THC on cognitive-inhibitory functions dependent on ventromedial vs. dorsolateral frontal cortex in monkeys and rats will be examined. In Aim 2, we will investigate the effects of drug exposure on incentive motivation using stimulus-reward learning and conditioned reinforcement, and expand these studies to monkeys and cocaine self-administering rats. An additional goal is to determine whether these drug-induced behavioral changes are associated with alterations in DA/PKA-regulated signaling pathways in cortico-limbic-striatal regions and correlate putative molecular changes with behavior. We propose to focus on the DA/PKA-regulated protein DARPP-32 because it can be used to assess both inhibition and amplification of DA/PKA signaling, and it is expressed in cortical-limbic as well as striatal regions. Aim 3 will directly test the hypothesis that reduced cortical PKA activity and enhanced limbic-striatal PKA activity can mimic the effects of prior drug exposure using local infusions of PKA inhibitors/activators and examine if drug-induced deficits can be reversed by infusions of PKA modulators.