Cocaine addiction: neuropharmacological mechanisms of compulsive cocaine use

可卡因成瘾：强迫性使用可卡因的神经药理学机制

• 批准号: 8576822
• 负责人: WENLIN SUN
• 金额: $ 28.5万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8576822
• 关键词: Achievement; American Psychiatric Association; Amygdaloid structure; Behavior; Behavior Control; Behavioral Mechanisms; Brain; Cell Nucleus; Chronic; Cocaine; Cocaine Dependence; Data; Development; Drug Targeting; Family; Goals; Habits; Impairment; Knowledge; Lead; Mediating; Midbrain structure; Molecular; Morale; Motivation; Nature; Obsessive compulsive behavior; Pharmaceutical Preparations; Pharmacotherapy; Play; Process; Psychological reinforcement; Punishment; Regulation; Research; Rewards; Role; Self Administration; Societies; Stress; Substantia nigra structure; Testing; Uncertainty; Up-Regulation; Wolves; Work; base; biological adaptation to stress; cocaine use; dopaminergic neuron; drug of abuse; habit learning; neural circuit; neuromechanism; novel; public health relevance; receptor

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.

描述（由申请人提供）： 强迫性可卡因使用，定义为尽管造成毁灭性后果但仍继续使用可卡因，是可卡因成瘾的一个定义特征。研究重点是了解长期使用可卡因如何改变涉及奖励、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可卡因成瘾。在识别这些改变背后的分子变化方面已经取得了巨大进展，这些变化对可卡因使用的增加至关重要。尽管取得了这些成就，但尚未成功开发出有效控制可卡因强迫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监管密切相关的其他机制。尽管成瘾者充分意识到可卡因的可怕后果，但他们仍然继续使用可卡因，这将阻止正常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，削弱可卡因使用的负面后果诱导抑制所涉及的大脑机制是可卡因成瘾的强迫方面的基本机制。尽管增强奖励、强化、动机效应、压力反应或习惯性可卡因使用可能有助于减少可卡因使用负面后果的调节，但它们不会介导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此类行为的机制。本申请的目的是确定长期使用可卡因导致的可卡因寻求行为抑制的负面后果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 将确定导致强迫性可卡因寻求行为的关键行为机制。特别是，我们将重点关注与通过负面后果抑制可卡因寻求行为至关重要的惩罚过程。目标 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。目标 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，并确定长期使用可卡因如何损害神经回路的功能，从而诱发强迫性可卡因寻求行为。此应用程序中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。这种新颖的观点无疑将刺激对其他滥用药物或其他强迫行为的强迫使用机制的研究。