Tacrine Effects on Cocaine Self-Administration and Pharmacokinetic Measures

他克林对可卡因自我给药的影响和药代动力学测量

• 批准号: 8113822
• 负责人: KENNETH W. GRASING
• 金额: $ 19.17万
• 依托单位: MIDWEST VETERANS' BIOMEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113822
• 关键词: Acetylcholine; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Adverse effects; Affect; Alzheimer' s Disease; Animals; Anxiety; Appetitive Behavior; Attenuated; Behavioral; Biological Availability; Brain; Butyrylcholinesterase; Cardiotoxicity; Cardiovascular Physiology; Cholinergic Receptors; Cholinesterase Inhibitors; Chronic; Cocaine; Cocaine Users; Data; Dopamine; Dose; Double-Blind Method; Drug Combinations; Drug Kinetics; Drug toxicity; Effectiveness; Evaluation; Hepatotoxicity; Human; Individual; Injection of therapeutic agent; Inpatients; Intravenous; Laboratories; Laboratory Animals; Lead; Learning; Measures; Memory; Metabolism; Methods; Monitor; Monoamine Oxidase Inhibitors; Moods; Motivation; Neurons; Nucleus Accumbens; Oral; Participant; Patients; Pharmaceutical Preparations; Placebo Control; Placebos; Plasma; Psychostimulant dependence; Randomized; Rattus; Relapse; Relative (related person); Self Administration; Self-Administered; Signal Transduction; Synapses; System; Tacrine; Toxic effect; Urine; Variant; Veins; Ventral Tegmental Area; attenuation; base; cholinergic; clinical efficacy; clinically relevant; cocaine use; craving; design; disorder later incidence prevention; donepezil; drug reinforcement; human subject; improved; inhibitor/antagonist; medication compliance; monoamine; motivated behavior; neuronal cell body; preference; prevent; reinforced behavior; rivastigmine; stimulant abuse; substance abuse treatment

DESCRIPTION (provided by applicant): Reinforcing effects of cocaine are believed to arise through release of dopamine (DA) at the nucleus accumbens by neurons in the ventral tegmental area. Activation of cholinergic receptors on the cell bodies of these neurons can enhance DA release. Elevated levels of acetylcholine (ACh) in the nucleus accumbens may also serve to inhibit appetitive behaviors. Cholinesterase inhibitors such as tacrine increase synaptic levels of ACh by preventing its inactivation by acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE), and can improve learning and memory. In animals, cholinesterase inhibitors can attenuate cocaine self-administration and conditioned place preference. Tacrine is a centrally acting, reversible inhibitor of AChE and BuChE that is approved for treatment of Alzheimer's disease. In addition to its effects on the cholinergic system, tacrine can potentiate the actions of monoamines, including DA. Although use of tacrine has declined because of requirements for monitoring of potential liver toxicity and pharmacokinetics that necessitate multiple daily doses, it is more potent than other cholinesterase inhibitors in attenuating cocaine self-administration in animals. Pretreatment with tacrine can produce long-lasting reductions in cocaine-reinforced behavior in rats, described as persistent attenuation (cocaine self-administration is decreased by more than 80% over a period of three days during which no additional cholinesterase inhibitor is administered, see Figure 1). No previous studies have evaluated whether tacrine can modify the effects of cocaine in humans. Rationale To our knowledge, tacrine is the only compound that can produce persistent attenuation in rats treated with clinically relevant doses. If similar effects were observed in humans, this would lead to an important paradigm shift for substance abuse treatment, in that large reductions in cocaine-reinforced behavior could be produced without the need for continuous dosing with a medication. This scenario could remove the requirement for continued compliance with oral dosing in some patients with its associated potential for toxicity. Specific Aims: 1. Evaluate whether tacrine treatment causes persistent attenuation of cocaine-reinforced behavior in humans. 2. Determine the effectiveness of pretreatment with tacrine in attenuating cocaine-induced craving. 3. Evaluate plasma levels of cocaine and characterize the bioavailability of tacrine in individual patients. Methods This is a randomized, double-blind, double-dummy, placebo-controlled, inpatient, single-center, parallel-group evaluation of the potential for oral tacrine to modify cocaine self-administration, cocaine-induced craving, and the pharmacokinetics of cocaine and tacrine. Forty non-treatment-seeking, regular cocaine users will receive nine days of double-blind treatment with oral placebo or tacrine (increased to 160 mg daily). To evaluate the occurrence of persistent attenuation, the subjective and reinforcing effects of intravenous cocaine will be determined during oral treatment and three days following its discontinuation. PUBLIC HEALTH RELEVANCE: No medications are currently available for treatment of psychostimulant addiction, a compulsive preoccupation with use of cocaine and related compounds. Tacrine, a medication that is currently prescribed for Alzheimer's disease, can decrease the amount of cocaine injections that laboratory animals choose to inject by vein. This project will determine if tacrine can also decrease cocaine-motivated behavior for human subjects in a laboratory setting.

描述（由申请人提供）：据信可卡因的增强作用是通过神经元在腹侧段区域的神经元在伏隔核释放（DA）而产生的。这些神经元细胞体上胆碱能受体的激活可以增强DA释放。伏隔核中乙酰胆碱水平升高也可能有助于抑制食用行为。胆碱酯酶抑制剂（例如他四折抑制剂）通过防止其乙酰胆碱酯酶（ACHE）或丁乙烯酯酶（Buche）的灭活来增加ACH的突触水平，并可以改善学习和记忆力。在动物中，胆碱酯酶抑制剂可以减弱可卡因的自我管理和条件的位置偏好。他的ACHE和BUCHE的中央作用，可逆的抑制剂被批准用于治疗阿尔茨海默氏病。除了其对胆碱能系统的影响外，他的他的他还可以增强包括DA在内的单胺的作用。尽管需要使用多种每日剂量的潜在肝脏毒性和药代动力学来监测潜在的肝脏毒性和药代动力学的使用情况下有所下降，但比其他胆碱酯酶抑制剂在减弱动物中可卡因自给自足时更有效。用四折治疗可以在大鼠中可卡因强化行为的长期降低，被描述为持续的衰减（可卡因自我给药在三天内降低了80％以上，在此期间，没有其他其他胆碱酯酶抑制剂抑制剂被施用，请参见图1）。以前的研究没有评估他的四折改变可卡因在人类中的影响。据我们所知，他是唯一可以在接受临床相关剂量治疗的大鼠中持续衰减的唯一化合物。如果在人类中观察到类似的影响，这将导致药物滥用治疗的重要范式转移，因为可以产生可卡因增强行为的大量降低，而无需用药物连续服用。这种情况可以消除某些具有相关毒性潜力的患者的持续遵守口服剂量的要求。具体目的：1。评估他的四折治疗是否导致人类可卡因增强行为的持续衰减。 2。确定他用他折磨可卡因引起的渴望预处理预处理的有效性。 3。评估可卡因的血浆水平，并表征单个患者中他的生物利用度。方法这是一种随机，双盲，双肢，安慰剂对照，住院，单中心的，平行组评估口服他的胃痛的潜力，以改变可卡因自我给药，可卡因诱导的cr虫，以及可卡因和cocaine and cocaine和tactarine的药代动力学。四十张非治疗方法，常规可卡因使用者将接受9天的双盲治疗，以口服安慰剂或他的他的身份（每天增加到160毫克）。为了评估持续衰减的发生，将在口服治疗期间和中断后三天确定静脉可卡因的主观和增强作用。 公共卫生相关性：目前尚无用于治疗心理刺激成瘾的药物，这是使用可卡因和相关化合物的强迫性群体。他的克林是目前针对阿尔茨海默氏病处方的药物，可以减少实验动物选择用静脉注射的可卡因注射量。该项目将确定他在实验室环境中对人类受试者的可卡因动机行为是否也可以减少。