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，受试者偶尔使用毒品并最终从非依赖性药物使用过渡到强迫性药物使用成瘾。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。尽管在理解转变为可卡因依赖的神经生物学机制方面取得了重大进展，但没有药物治疗可卡因依赖。最近，丘脑下核的深部脑刺激被认为是治疗强迫症的一种手术策略，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。丘脑下核是一个属于基底神经节的大脑结构，通常与运动控制有关，它在药物成瘾者的关键认知过程中起着关键作用。这项提议的总体目标是使用一种新的、潜在的突破性治疗方法来治疗可卡因成瘾，使用一种创新的神经外科方法，这种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的动物模型有关。初步结果表明，丘脑下核的损伤限制了依赖大鼠可卡因摄入量的增加，而丘脑下核的深部脑刺激降低了大鼠可卡因的动机。在依赖大鼠中，STN的深部脑刺激是否会逆转可卡因摄入的增加并防止可卡因寻求的复发尚不清楚。该建议的具体目标是确定是否有可能逆转可卡因的升级（SpA1），并通过对可卡因依赖大鼠的丘脑下核进行深部脑刺激来防止药物、压力和线索诱导的可卡因寻求恢复（SpA2）。这些研究将提供关于丘脑下核在与可卡因依赖相关的强迫行为中的作用的新发现，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.