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伏隔核释放多巴胺（DA）而产生的。激活这些神经元细胞体上的胆碱能受体可促进DA的释放。伏隔核中乙酰胆碱（ACh）的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）或丁基胆碱酯酶（BuChE）使乙酰胆碱酯酶失活，增加突触乙酰胆碱水平，并能改善学习和记忆。在动物中，胆碱酯酶抑制剂可以减弱可卡因的自我给药和条件性位置偏好。Tacrine是一种中枢作用的、可逆的AChE和BuChE抑制剂，已被批准用于治疗阿尔茨海默病。除了对胆碱能系统的作用外，他克林还能增强单胺类药物的作用，包括DA。尽管由于需要监测潜在的肝毒性和需要每日多次给药的药代动力学，他克林的使用已经减少，但在减少动物体内可卡因自我给药方面，他克林比其他胆碱酯酶抑制剂更有效。用他克林预处理可以使大鼠的可卡因强化行为长期减少，被描述为持续衰减（在没有额外使用胆碱酯酶抑制剂的情况下，可卡因自我给药在三天内减少80%以上，见图1）。以前没有研究评估过他克林是否能改变人类对可卡因的影响。据我们所知，他克林是唯一一种在临床相关剂量的大鼠体内能产生持续衰减的化合物。如果在人类身上观察到类似的效果，这将导致药物滥用治疗的重要范式转变，因为可以在不需要持续服用药物的情况下大幅减少可卡因强化行为。这种情况可以消除一些患者持续遵守口服给药的要求，因为口服给药有潜在的毒性。具体目标：1；评估他克林治疗是否会导致人类可卡因强化行为的持续衰减。2. 确定他克林预处理在减轻可卡因诱导渴求中的有效性。3. 评估血浆可卡因水平，并确定个体患者他克林的生物利用度。方法随机、双盲、双假、安慰剂对照、住院、单中心、平行组评价口服他克林改变可卡因自我给药、可卡因诱导渴望以及可卡因和他克林药代动力学的潜力。40名不寻求治疗的常规可卡因使用者将接受9天的口服安慰剂或他克林双盲治疗（增加到每天160毫克）。为了评估持续衰减的发生，静脉注射可卡因的主观和强化效应将在口服治疗期间和停药后三天确定。

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.