Tacrine Effects on Cocaine Self-Administration and Pharmacokinetic Measures

描述（由申请人提供）：可卡因的强化作用被认为是通过腹侧被盖区神经元在延髓核释放多巴胺（DA）而产生的。这些神经元胞体上的胆碱能受体的激活可增强DA的释放。丘脑核中乙酰胆碱（ACh）水平升高也可能抑制食欲行为。胆碱酯酶抑制剂（如他克林）通过防止乙酰胆碱酯酶（AChE）或丁酰胆碱酯酶（BuChE）失活来增加ACh的突触水平，并可以改善学习和记忆。在动物中，胆碱酯酶抑制剂可以减弱可卡因自我给药和条件性位置偏爱。他克林是一种中枢作用的可逆AChE和BuChE抑制剂，被批准用于治疗阿尔茨海默病。除了它对胆碱能系统的影响，他克林可以增强单胺类，包括DA的行动。虽然使用他克林已经下降，因为需要监测潜在的肝毒性和药代动力学，需要每天多次给药的要求，它是更有效的比其他胆碱酯酶抑制剂在衰减可卡因自我管理的动物。用他克林预处理可使大鼠的可卡因强化行为产生持久的减少，被描述为持续性衰减（可卡因自我给药在三天内减少80%以上，在此期间不给予额外的胆碱酯酶抑制剂，见图1）。以前没有研究评估他克林是否可以改变可卡因对人类的影响。据我们所知，他克林是唯一的化合物，可以产生持久的衰减在大鼠与临床相关剂量治疗。如果在人类中观察到类似的效果，这将导致药物滥用治疗的重要范式转变，因为可卡因强化行为的大量减少可以在不需要连续服用药物的情况下产生。这种情况可以消除某些患者持续依从口服给药的要求，并消除其相关的潜在毒性。具体目标：1。评估他克林治疗是否会导致可卡因强化行为的持续衰减。2.确定他克林预处理在减弱可卡因诱导的渴求中的有效性。3.评价可卡因的血浆水平和他克林在个体患者中的生物利用度。方法本研究采用随机、双盲、双模拟、安慰剂对照、住院、单中心、平行分组的研究方法，评价口服他克林对可卡因自我给药、可卡因诱发的渴求以及可卡因和他克林的药代动力学的影响。40名非寻求治疗的可卡因常规使用者将接受为期9天的口服安慰剂或他克林（增加至每天160毫克）双盲治疗。为了评价持续衰减的发生率，将在口服治疗期间和停药后3天测定静脉注射可卡因的主观和强化效应。 公共卫生相关性：目前没有药物可用于治疗精神兴奋剂成瘾，这是一种对使用可卡因和相关化合物的强迫性专注。他克林，一种目前用于治疗阿尔茨海默病的药物，可以减少实验室动物选择静脉注射的可卡因注射量。这个项目将确定他克林是否也可以在实验室环境中减少人类受试者的可卡因动机行为。

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.