Effects of Deep Brain Stimulation on Compulsive Drug Intake

描述（由申请人提供：可卡因成瘾是一种慢性复发性疾病，其中受试者间歇性地服用药物，并最终从非依赖性药物使用转变为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表征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转变背后的神经生物学机制方面取得了重大进展，但目前还没有最近，有人提出对丘脑底核进行深部脑刺激是治疗强迫症的一种手术策略，但从未在强迫性吸毒和药物寻求的临床前模型中进行过测试。使用创新的神经外科方法治疗可卡因成瘾的新的、潜在的突破性治疗方法，在其他大脑和精神疾病中显示出显着的效果，与强迫性可卡因摄入和可卡因复发高度相关的动物模型有关。初步结果表明，丘脑底核的损伤限制了依赖大鼠的可卡因摄入量的增加，而丘脑底核的深层脑刺激是否会降低大鼠对可卡因的动机尚不清楚。 STN 的大脑刺激将逆转可卡因摄入量的增加并防止可卡因依赖性大鼠复发。该提案的具体目标是确定是否有可能逆转可卡因 (SpA1) 的增加，并通过对可卡因依赖性大鼠的丘脑底核进行深部脑刺激来防止药物、压力和提示诱导的可卡因依赖性恢复 (SpA2)。底丘脑核与可卡因依赖相关的强迫性相关，可能为开发一般药物成瘾的创新治疗方法开辟新途径。 公共卫生相关性：尽管在了解毒瘾转变的神经生物学机制方面取得了重大进展，但尚无可用的药物治疗方法。该提案的总体目标是使用新的、潜在突破性的治疗方法来治疗可卡因成瘾，即通过对丘脑底核进行深部脑刺激，与强迫性可卡因摄入和可卡因寻求复发高度相关的动物模型相关。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基础的新发现，对药物滥用具有直接的转化影响，并可能为开发药物成瘾的创新治疗方法开辟新的途径。

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.