Cocaine addiction: neuropharmacological mechanisms of compulsive cocaine use

描述（由申请人提供）：强迫性可卡因使用，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典型特征。研究的重点是了解慢性可卡因使用如何改变涉及奖励、强化、动机、习惯学习、压力的大脑过程，以及这些改变如何导致强迫性可卡因使用。在查明这些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着至关重要的作用。尽管取得了这一成就，但尚未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，需要扩大研究范围，以寻找与可卡因使用调节密切相关的其他机制。事实上，瘾君子在完全意识到可怕后果的情况下仍然继续使用可卡因，这将阻止正常人从事任何导致这种后果的行为，这表明，在这种威慑作用中，大脑功能受到了损害。因此，削弱参与消极后果诱导的可卡因使用抑制的大脑机制是可卡因成瘾强迫性方面的基本机制。虽然奖励、强化、激励效应、压力反应或习惯样可卡因使用的增强可能有助于减少可卡因使用负面后果的调节，但它们并没有调节可卡因使用的强迫性方面，因为它们没有削弱这种行为的负面后果介导抑制的潜在机制。本应用程序的目的是确定慢性可卡因使用诱导的消极后果诱导的可卡因寻求行为抑制减弱的神经药理学机制。因此，这项研究有可能在理解可卡因成瘾的强迫性本质背后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，以开发抗可卡因成瘾药物疗法。为此，提出了三个具体目标。目的1将确定对强迫性可卡因寻求行为至关重要的行为机制。特别是，我们将重点关注惩罚过程，这一过程对通过负面后果抑制可卡因寻求行为至关重要。目的2将确定对强迫性可卡因寻求行为至关重要的神经药理学机制。目的3将确定参与惩罚诱导的可卡因寻求行为抑制的神经回路，并确定慢性可卡因使用如何损害回路诱导强迫性可卡因寻求行为的功能。这个应用程序的信息将把我们对可卡因使用监管的看法从积极监管的单一角度转变为一个新的、更复杂的角度，即积极和消极后果的协调监管。这种新颖的视角无疑将激发对其他药物滥用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.