Tacrine Effects on Cocaine Self-Administration and Pharmacokinetic Measures

描述(申请人提供)：可卡因的增强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。激活这些神经元胞体上的胆碱能受体可以促进DA的释放。伏隔核中乙酰胆碱(ACh)水平的升高也可能有助于抑制食欲行为。胆碱酯酶抑制剂如他克林通过阻止乙酰胆碱酯酶(AChE)或丁基胆碱酯酶(BuChE)使ACh失活而增加其突触水平，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的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影响外，他克林还可以增强包括DA在内的单胺类物质的作用。尽管他克林的使用已经减少，因为需要监测潜在的肝脏毒性和药代动力学，这需要每天多次服用，但在减少动物体内的可卡因自身给药方面，它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，称为持续衰减(在不使用额外胆碱酯酶抑制剂的三天内，可卡因自身给药减少80%以上，见图1)。之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，他克林是唯一一种可以在临床相关剂量治疗的大鼠中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，因为在不需要持续服药的情况下，可卡因强化行为的大幅减少可以产生。这种情况可能会消除一些患者继续遵守口服剂量的要求，因为这可能会产生毒性。具体目标：1.评估他克林治疗是否导致人类可卡因强化行为的持续减弱。2.确定他克林预处理对减轻可卡因诱导的渴求的效果。3.评估血浆可卡因水平，并表征他克林在个体患者中的生物利用度。方法采用随机、双盲、双模拟、安慰剂对照、住院、单中心、平行分组的方法，评价口服他克林改变可卡因自身给药、可卡因诱导的渴求以及可卡因和他克林的药代动力学的可能性。40名不寻求治疗的常规可卡因使用者将接受为期9天的双盲治疗，口服安慰剂或他克林(增加到每天160毫克)。为了评估持续性衰减的发生，将在口服治疗期间和停药后三天测定静脉注射可卡因的主观和强化效果。 与公共卫生相关：目前还没有治疗精神刺激性成瘾的药物，这是一种使用可卡因和相关化合物的强迫症。他克林是一种目前用于阿尔茨海默病的处方药，可以减少实验室动物选择通过静脉注射的可卡因注射量。该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.