Effects of Deep Brain Stimulation on Compulsive Drug Intake

深部脑刺激对强迫性药物摄入的影响

• 批准号: 8114767
• 负责人: George F. Koob
• 金额: $ 24.85万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114767
• 关键词: Abstinence; Animal Model; Animals; Basal Ganglia; Behavioral; Biological Neural Networks; Brain; Brain Diseases; Brain Mapping; Cerebrum; Chronic; Cocaine; Cocaine Dependence; Cognitive; Cues; Deep Brain Stimulation; Dependence; Development; Disease; Drug Addiction; Drug abuse; Drug usage; Dystonia; Eagles; Frequencies; Funding; Human; Impulsivity; Incentives; Intake; Lesion; Mental disorders; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Obsessive-Compulsive Disorder; Operative Surgical Procedures; Parkinson Disease; Pharmaceutical Preparations; Pharmacological Treatment; Pre-Clinical Model; Process; Rattus; Recruitment Activity; Relapse; Resistance; Rewards; Role; STN stimulation; Stress; Structure; Structure of subthalamic nucleus; Techniques; Testing; Therapeutic; Time; Tremor; addiction; alternative treatment; chronic pain; cocaine relapse prevention; cocaine use; craving; drug abstinence; drug craving; innovation; motivated behavior; motor control; nervous system disorder; neurobiological mechanism; prevent; treatment strategy

DESCRIPTION (provided by applicant: Cocaine addiction is a chronic relapsing disorder in which subjects episodically administer the drug and ultimately transition from nondependent drug use to the compulsive drug use of addiction. A progressive increase in the frequency and intensity of cocaine use, and a high propensity to relapse after abstinence are two of the major behavioral phenomenon that characterizes the development of cocaine addiction. Despite major advances in understanding the neurobiological mechanisms underlying the transition to cocaine dependence, there are no pharmacological treatments for cocaine dependence. Recently, deep brain stimulation of the subthalamic nucleus has been proposed has a surgical strategy for obsessive-compulsive disorders, but it has never been tested in preclinical models of compulsive drug taking and drug seeking. The subthalamic nucleus, a cerebral structure belonging to the basal ganglia and classically associated with motor control, is critically involved in key cognitive processes that become dysfunctional in subjects with drug addiction. The overall objective of this proposal is to use a new, potentially groundbreaking therapeutic approach for the treatment of cocaine addiction using an innovative neurosurgical approach that has shown remarkable results in other brain and mental disorders, associated with highly relevant animal models of compulsive cocaine intake and relapse to cocaine seeking. Preliminary results show that lesion of the subthalamic nucleus limits the escalation of cocaine intake in dependent rats, and that deep brain stimulation of the subthalamic nucleus decreases the motivation for cocaine in rats. Unknown is whether deep brain stimulation of the STN will reverse the escalation of cocaine intake and prevent relapse to cocaine seeking in dependent rats. The specific objectives of this proposal are to determine whether it is possible to reverse the escalation of cocaine (SpA1), and to prevent drug-, stress-, and cue-induced reinstatement to cocaine seeking (SpA2) using deep brain stimulation in the subthalamic nucleus in cocaine dependent rats. These studies will provide new findings on the role of the subthalamic nucleus in the compulsivity associated with cocaine dependence and may open new avenues for the development of innovative treatments of drug addiction in general. PUBLIC HEALTH RELEVANCE: Despite major advances in understanding the neurobiological mechanisms underlying the transition to drug addiction there are no pharmacological treatments available. The overall objective of this proposal is to use new, potentially groundbreaking therapeutic approaches for cocaine addiction using deep brain stimulation of the subthalamic nucleus, associated with highly relevant animal models of compulsive cocaine intake and relapse to cocaine seeking. These studies will provide new findings on the neurobiological substrates of compulsive cocaine taking and craving, have direct translational implications for drug abuse, and may open new avenues for the development of innovative treatments of drug addiction in general.

描述（由申请方提供）：可卡因成瘾是一种慢性复发性疾病，受试者间歇性给药，最终从非依赖性药物使用过渡到成瘾的强迫性药物使用。可卡因使用频率和强度的逐渐增加以及戒断后复发的高倾向是可卡因成瘾发展的两个主要行为现象。尽管在理解可卡因依赖性转变的神经生物学机制方面取得了重大进展，但尚无可卡因依赖性的药物治疗。最近，丘脑底核的脑深部电刺激被提出是一种治疗强迫症的手术策略，但它从未在强迫性药物服用和药物寻求的临床前模型中进行过测试。丘脑底核是一种属于基底神经节的大脑结构，通常与运动控制相关，它与药物成瘾受试者的关键认知过程密切相关。该提案的总体目标是使用一种新的、可能具有开创性的治疗方法来治疗可卡因成瘾，这种方法使用一种创新的神经外科方法，在其他大脑和精神疾病中显示出显著的效果，与强迫性可卡因摄入和可卡因寻求复发的高度相关动物模型相关。初步结果表明，丘脑底核的病变限制了依赖性大鼠可卡因摄入量的增加，丘脑底核的脑深部刺激降低了大鼠可卡因的动机。目前尚不清楚的是，脑深部电刺激是否会逆转可卡因摄入量的上升，并防止依赖性大鼠再次寻求可卡因。本提案的具体目标是确定是否有可能逆转可卡因（SpA1）的升级，并在可卡因依赖大鼠的丘脑底核中使用脑深部刺激来防止药物、压力和线索诱导的可卡因寻求（SpA2）的恢复。这些研究将提供关于丘脑底核在可卡因依赖相关强迫性中的作用的新发现，并可能为开发一般药物成瘾的创新治疗开辟新途径。 公共卫生相关性：尽管在理解药物成瘾的神经生物学机制方面取得了重大进展，但仍然没有可用的药物治疗。该提案的总体目标是使用新的、可能具有突破性的可卡因成瘾治疗方法，使用丘脑底核的脑深部刺激，与强迫性可卡因摄入和可卡因寻求复发的高度相关动物模型相关。这些研究将提供关于强迫性可卡因服用和渴望的神经生物学底物的新发现，对药物滥用有直接的翻译影响，并可能为药物成瘾的创新治疗的发展开辟新的途径。