Cocaine addiction: neuropharmacological mechanisms of compulsive cocaine use

描述(由申请人提供)：强制使用可卡因，定义为不顾破坏性后果继续使用可卡因，是可卡因成瘾的一个定义特征。研究的重点一直是了解长期使用可卡因可能会如何改变与奖励、强化、动机、习惯学习、压力有关的大脑过程，以及这种改变可能如何导致强制使用可卡因。在确定这种变化背后的分子变化方面取得了巨大进展，这些变化对增加可卡因的使用起到了至关重要的作用。尽管取得了这一成就，但没有成功开发出有效控制强迫性可卡因使用的药物疗法这一事实表明，这项研究需要扩大，以寻找与调节可卡因使用有关的其他关键机制。吸毒者尽管充分意识到可卡因的可怕后果，但仍继续使用可卡因，这将阻止普通人从事任何导致此类后果的行为，这一事实表明，与这种威慑作用密切相关的大脑功能存在损害。因此，削弱负面后果导致的可卡因使用抑制所涉及的大脑机制是可卡因成瘾强迫方面的基本机制。虽然增强的奖赏、强化、激励效应、压力反应或类似习惯的可卡因使用可能有助于减少可卡因使用的负面后果的调节，但它们不能调节可卡因使用的强迫方面，因为它们不会削弱负面后果介导的抑制这类行为的机制。这项应用的目的是确定慢性可卡因使用导致的负面后果诱导的抑制可卡因寻找行为的减弱的神经药理学机制。因此，这项研究有可能在了解可卡因成瘾强迫本质的大脑机制方面取得突破。这些知识可能会导致发现新的药物靶点，用于开发抗可卡因成瘾的药物疗法。为此，提出了三个具体目标。目标1将确定导致强迫性寻求可卡因行为的关键行为机制。特别是，我们将重点关注通过消极后果抑制寻求可卡因行为的关键惩罚过程。目的2将确定对强迫性寻求可卡因行为起关键作用的神经药理学机制。目的3将确定参与惩罚诱导的可卡因寻找行为抑制的神经回路，并确定长期使用可卡因如何损害诱导强迫性寻找可卡因行为的回路功能。这项申请的信息将把我们对可卡因使用监管的观点从积极监管的单一视角转变为通过积极和消极后果进行协调监管的新的、更复杂的视角。这种新颖的视角无疑将促进对强迫使用其他滥用药物或其他强迫行为的机制的研究。

DESCRIPTION (provided by applicant): Compulsive cocaine use, defined as continued cocaine use despite the devastating consequences, is a defining feature of cocaine addiction. Research has been focusing on understanding how chronic cocaine use may alter the brain processes involved in reward, reinforcement, motivation, habit learning, stress and how such alterations may contribute to compulsive cocaine use. Tremendous progresses have been made in identifying the molecular changes underlying such alterations and these changes critically contribute to enhanced cocaine use. Despite the achievement, the fact that no pharmacotherapies have been successfully developed to effectively control compulsive cocaine use indicates that the research needs to be broadened to look for other mechanisms critically involved in regulation of cocaine use. The fact that addicts continue cocaine use despite being fully aware of the dire consequences, which would deter normal people from engaging in any behavior that results in such consequences, suggests that there is impairment in the brain function critically involved in such deterrence. Thus, weakening the brain mechanism involved in negative consequence-induced inhibition of cocaine use is the fundamental mechanism underlying the compulsive aspect of cocaine addiction. Although enhanced rewarding, reinforcing, motivational effects, stress response or habit-like cocaine use may contribute to the decreased regulation by negative consequences of cocaine use, they do not mediate the compulsive aspect of cocaine use because they do not weaken the mechanism underlying negative consequence-mediated inhibition of such behavior. The goal of this application is to identify the neuropharmacological mechanisms underlying chronic cocaine use-induced weakening of negative consequence-induced inhibition of cocaine-seeking behavior. Thus, this study has the potential to make a breakthrough in understanding the brain mechanisms underlying the compulsive nature of cocaine addiction. Such knowledge likely leads to discovery of new drug targets for development of anti-cocaine addiction pharmacotherapies. To this end, three specific aims are proposed. Aim 1 will determine the behavioral mechanism critically contributing to compulsive cocaine-seeking behavior. In particular, we will focus on the punishment process that is critically involved in inhibition of cocaine-seeking behavior by negative consequences. Aim 2 will determine the neuropharmacological mechanisms critically contributing to compulsive cocaine-seeking behavior. Aim 3 will identify the neural circuit involved in punishment-induced inhibition of cocaine-seeking behavior and determine how chronic cocaine use impairs the function of the circuit to induce compulsive cocaine-seeking behavior. The information from this application will shift our view on regulation of cocaine use from the single perspective of positive regulation to a new, more sophisticated perspective of coordinated regulation by both positive and negative consequences. Such a novel perspective will no doubt stimulate research on the mechanisms compulsive use of other drugs of abuse or other compulsive behavior.