Effects of Deep Brain Stimulation on Compulsive Drug Intake

描述(申请人提供：可卡因成瘾是一种慢性复发性障碍，受试者间歇性地使用药物，最终从非依赖药物使用过渡到强制药物使用成瘾。可卡因使用频率和强度的逐渐增加，以及戒除后复发的高倾向，是可卡因成瘾发展的两个主要行为现象。尽管在理解向可卡因依赖转变的神经生物学机制方面取得了重大进展，但目前还没有针对可卡因依赖的药物治疗方法。最近，丘脑底核深部脑刺激已被提出治疗强迫症的手术策略，但它从未在强迫吸毒和寻求药物的临床前模型中进行测试。丘脑底核是一种属于基底节的大脑结构，经典地与运动控制有关，它与关键的认知过程有关，这些过程在吸毒成瘾的受试者中变得异常。这项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，使用一种创新的神经外科方法，该方法已在其他大脑和精神障碍中显示出显著效果，与强迫性可卡因摄取和复吸可卡因的高度相关的动物模型相关。初步结果显示，损毁丘脑底核限制了依赖大鼠对可卡因摄入量的增加，而丘脑底核脑深部刺激降低了大鼠对可卡因的动机。尚不清楚的是，STN的大脑深部刺激是否会逆转可卡因摄入量的上升，并防止依赖大鼠再次寻求可卡因。这项建议的具体目标是确定是否有可能逆转可卡因的升级(SpA1)，并防止药物、应激和线索诱导的可卡因寻求(SpA2)的恢复(SpA2)，方法是通过刺激可卡因依赖大鼠的丘脑底核。这些研究将为丘脑底核在与可卡因依赖相关的强迫症中的作用提供新的发现，并可能为开发创新的药物成瘾治疗开辟新的途径。 与公共卫生相关：尽管在了解向药物成瘾转变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方法。这项提案的总体目标是使用新的、可能具有开创性的治疗方法，通过刺激丘脑底核的深部大脑，与强迫性吸食可卡因和复发寻求可卡因的高度相关的动物模型相关。这些研究将提供有关强迫性可卡因服用和渴求的神经生物学基础的新发现，对药物滥用具有直接的翻译意义，并可能为开发创新的药物成瘾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.